Tricyclic diazepine vasopressin antagonists and oxytocin antagonists

ABSTRACT

Tricyclic diazepines of the formula: ##STR1## wherein A, B, D, E, F, Y and Z are defined in the specification which compounds have vasopressin and oxytocin antagonist activity.

This is a continuation-in-part of application Ser. No. 08/468,737, filedJun. 6, 1995, U.S. Pat. No. 5,624,923 which is a Divisional ofapplication Ser. No. 08/254,822, U.S. Pat. No. 5,516,774 filed Jun. 13,1994, which is a continuation-in-part of application Ser. No.08/100,004, filed Jul. 29, 1993, abandoned.

FIELD OF THE INVENTION

This invention relates to new tricyclic non-peptide vasopressinantagonists which are useful in treating conditions where decreasedvasopressin levels are desired, such as in congestive heart failure, indisease conditions with excess renal water reabsorption and conditionswith increased vascular resistance and coronary vasoconstriction.

BACKGROUND OF THE INVENTION

Vasopressin is released from the posterior pituitary either in responseto increased plasma osmolarity detected by brain osmoreceptors ordecreased blood volume and blood pressure sensed by low-pressure volumereceptors and arterial baroreceptors. The hormone exerts its actionsthrough two well defined receptor subtypes: vascular V₁ and renalepithelial V₂ receptors. Vasopressin-induced antidiuresis, mediated byrenal epithelial V₂ receptors, helps to maintain normal plasmaosmolarity, blood volume and blood pressure.

Vasopressin is involved in some cases of congestive heart failure whereperipheral resistance is increased. V₁ antagonists may decrease systemicvascular resistance, increase cardiac output and prevent vasopressininduced coronary vasoconstriction. Thus, in conditions with vasopressininduced increases in total peripheral resistance and altered local bloodflow, V₁ -antagonists may be therapeutic agents.

The blockade of V₂ receptors may be useful in treating diseasescharacterized by excess renal re-absorption of free water. Antidiuresisis regulated by the hypothalamic release of vasopressin (antidiuretichormone) which binds to specific receptors on renal collecting tubulecells. This binding stimulates adenylyl cyclase and promotes thecAMP-mediated incorporation of water pores into the luminal surface ofthese cells. V₂ antagonists may correct the fluid retention incongestive heart failure, liver cirrhosis, nephrotic syndrome, centralnervous injuries, lung disease and hyponatremia.

Elevated vasopressin levels occur in congestive heart failure which ismore common in older patients with chronic heart failure. In patientswith hyponatremic congestive heart failure and elevated vasopressinlevels, a V₂ antagonist may be beneficial in promoting free waterexcretion by antagonizing the action of antiduretic hormone. On thebasis of the biochemical and pharmacological effects of the hormonesantagonists of vasopressin are expected to be therapeutically useful inthe treatment and/or prevention of hypertension, cardiac insufficiency,coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis,congestive heart failure, nephrotic syndrome, brain edema, cerebralischemia, cerebral hemorrhage-stroke, thrombosis-bleeding, abnormalstates of water retention.

The following prior art references describe peptide vasopressinantagonists; M. Manning et al., J. Med. Chem., 35, 382(1992); M. Manninget al., J. Med. Chem., 35, 3895(1992); H. Gavras and B. Lammek, U.S.Pat. No. 5,070,187 (1991); M. Manning and W. H. Sawyer, U.S. Pat. No.5,055,448(1991); F. E. Ali, U.S. Pat. No. 4,766,108(1988); R. R. Ruffoloet al., Drug News and Perspective, 4(4), 217, (May)(1991). P. D.Williams et al., have reported on potent hexapeptide oxytocinantagonists J. Med. Chem., 35, 3905(1992)! which also exhibit weakvasopressin antagonist activity in binding to V₁ and V₂ receptors.Peptide vasopressin antagonists suffer from a lack or oral activity andmany of these peptides are not selective antagonists since they alsoexhibit partial agonist activity.

Non-peptide vasopressin antagonists have recently been disclosed, Y.Yamamura et al., Science, 252, 579(1991); Y. Yamamura et al., Br. J.Pharmacol., 105, 787(1992), Ogawa et al., (Otsuka Pharm Co., LTD.) EP0514667-A1; JP 04154765-A; EPO 382185-A2; and W09105549. Carbostyrilderivatives and pharmaceutical compositions containing the same aredisclosed by Ogawa et al., (Otsuka Pharm. Co.) in EP 470514A.Non-peptide oxytocin and vasopressin antagonist have been disclosed byMerck and Co.; M. G. Bock and P. D. Williams, EP 0533242A; M. G. Bock etal., EP 0533244A; J. M. Erb, D. F. Verber, P. D. Williams, EP0533240A;K. Gilbert et al., EP 0533243A.

Premature birth can cause infant health problems and mortality and a keymediator in the mechanism of labor is the peptide hormone oxytocin. Onthe basis of the pharmacological action of oxytocin, antagonists of thishormone are useful in the prevention of preterm labor, B. E. Evans etal., J. Med. Chem., 35, 3919(1992), J. Med. Chem., 36, 3993(1993) andreferences therein. The compounds of this invention are antagonists ofthe peptide hormone oxytocin and are useful in the control of prematurebirth.

The present invention relates to novel tricyclic derivatives whichexhibit antagonist activity at V₁ and/or V₂ receptors and exhibit invivo vasopressin antagonist activity. The compounds also exhibitantagonists activity of oxytocin receptors.

SUMMARY OF THE INVENTION

This invention relates to new compounds selected from those of thegeneral formula I: ##STR2## wherein Y is a moiety selected from;--(CH₂)_(n) -- wherein n is an integer from 0 to 2, ##STR3## A--B is amoiety selected from ##STR4## wherein m is an integer from 1 to 2provided that when Y is --(CH₂)_(n) -- and n is 2, m may also be zeroand when n is zero, m may also be three, provided also that when Y is--(CH₂)_(n) -- and n is 2, m may not be two;

and the moiety: ##STR5## represents: (1) fused phenyl or fusedsubstituted phenyl optionally substituted by one or two substituentsselected from (C₁ -C₃)lower alkyl, halogen, amino, (C₁ -C₃)lower alkoxyor (C₁ -C₃)lower alkylamino; (2) a 5-membered aromatic (unsaturated)heterocyclic ring having one heteroatom selected from O, N or S; (3) a6-membered aromatic (unsaturated) heterocyclic ring having one nitrogenatom; (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ringhaving two nitrogen atoms; (5) a 5-membered aromatic (unsaturated)heterocyclic ring having one nitrogen atom together with either oneoxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclicrings are optionally substituted by (C₁ -C₃)lower alkyl, halogen or (C₁-C₃)lower alkoxy;

the moiety: ##STR6## is a five membered aromatic(unsaturated) fusednitrogen containing heterocyclic ring wherein D, E and F are selectedfrom carbon or nitrogen and wherein the carbon atoms may be optionallysubstituted by a substituent selected from halogen, (C₁ -C₃)lower alkyl,hydroxy, --COCl₃, --COCF₃, ##STR7## --CHO, amino, (C₁ -C₃)lower alkoxy,(C₁ -C₃)lower alkylamino, CONH-lower alkyl(C₁ -C₃), and --CON loweralkyl(C₁ -C₃)!₂ ; q is one or two; R_(b) is independently selected fromhydrogen, --CH₃ or --C₂ H₅ ;

R³ is a moiety of the formula: ##STR8## wherein Ar is a moiety selectedfrom the group consisting of ##STR9## wherein X is selected from O, S,NH, NCH₃ and NCOCH₃ ; R⁴ is selected from hydrogen, lower alkyl(C₁ -C₃),--CO--lower alkyl(C₁ -C₃), ##STR10## --SO₂ lower alkyl(C₁ -C₃); R¹ andR² are selected from hydrogen, (C₁ -C₃)lower alkyl, (C₁ -C₃)lower alkoxyand halogen; R⁵ is selected from hydrogen, (C₁ -C₃)lower alkyl, (C₁-C₃)lower alkoxy and halogen;

R⁶ is selected from (a) moieties of the formulae: ##STR11## whereincycloalkyl is defined as C₃ -C₆ cycloalkyl, cyclohexenyl orcyclopentenyl; R_(a) is independently selected from hydrogen, --CH₃,--C₂ H₅, ##STR12## --(CH₂)_(q) --O-lower alkyl(C₁ -C₃) and --CH₂ CH₂ OH,q is one or two, and R₁, R₂ and R_(b) are as hereinbefore defined;

(b) a moiety of the formula: ##STR13## wherein R² is as hereinbeforedefined; (c) a moiety of the formula: ##STR14## wherein J is R_(a),lower alkyl(C₁ -C₈) branched or unbranched, lower alkenyl(C₁ -C₈)branched or unbranched, O-lower alkyl(C₁ -C₈) branched or unbranched,--O-lower alkenyl(C₁ -C₈) branched or unbranched, tetrahydrofuran,tetrahydrothiophene, or --CH₂ --K wherein K is (C₁ -C₃) lower alkoxy,halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ringmoiety: ##STR15## wherein D, E, F and G are selected from carbon ornitrogen and wherein the carbon atoms may be optionally substituted withhalogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl(C₁ -C₃), CHO,(C₁ -C₃)lower alkoxy, --CO₂ -lower alkyl(C₁ -C₃), and R_(a) and R_(b)are as hereinbefore defined;

(d) a moiety of the formula: ##STR16## wherein R_(a) and R_(b) are ashereinbefore defined and Ar' is selected from moieties of the formula:##STR17## wherein W' is selected from O, S, NH, N-lower alkyl(C₁ -C₃),NHCO-lower alkyl(C₁ -C₃), and NSO₂ lower alkyl(C₁ -C₃);

R⁷ is selected from hydrogen, lower alkyl(C₁ -C₃), halogen, O-loweralkyl(C₁ -C₃) and CF₃ ;

R⁸ and R⁹ are independently selected from hydrogen, lower alkyl(C₁ -C₃),--S-lower alkyl(C₁ -C₃), halogen, --NH-lower alkyl(C₁ -C₃), --OCF₃,--OH, --CN, --S--CF₃, --NO₂, --NH₂, O-lower alkyl(C₁ -C₃), ##STR18## andCF₃ and; R¹⁰ is selected from hydrogen, halogen and lower alkyl(C₁ -C₃),and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Within the group of the compounds defined by Formula I, certainsubgroups of compounds are broadly preferred. Broadly preferred arethose compounds wherein R₃ is the moiety: ##STR19## and Ar is selectedfrom the moiety ##STR20## wherein R⁵, R⁶ and R⁷ are as hereinbeforedefined.

Especially preferred are compounds wherein R³ is the moiety ##STR21## Aris selected from the moiety ##STR22## R⁶ is ##STR23## wherein cycloalkylis defined as C₃ -C₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

R_(a) and R_(b) are as hereinbefore defined;

and Ar' is selected from the moieties: ##STR24## wherein R⁸, R⁹ and W'are as hereinbefore defined.

Also especially preferred are compounds wherein Y in Formula I is--(CH₂)_(n) -- and n is zero or one; A--B is ##STR25## and R⁴, R⁵, R⁶,R⁷, R⁸, R⁹ and R¹⁰ are as hereinbefore defined; and m is an integer from1-2.

The most preferred of the compounds of Formula I are those wherein Y is--(CH₂)_(n) -- and n is one;

A--B is ##STR26## R₃ is the moiety ##STR27## Ar is the moiety ##STR28##R⁶ is ##STR29## --(CH₂)_(n) -cycloalkyl wherein cycloalkyl is defined asC₃ -C₆ cycloalkyl, cyclohexenyl or cyclopentenyl; R_(a) and R_(b) are ashereinbefore defined;

and Ar' is ##STR30## wherein R⁵ R⁸ and R⁹ are as previously defined.

The most hilly broadly preferred of the compounds of Formula I are thosewherein Y is --(CH₂)_(n) -- and n is zero or one; wherein the moiety##STR31## is a fused phenyl, substituted phenyl, thiophene, furan,pyrrole or pyridine ring;

A--B is ##STR32## m is one when n is one and m is two when n is zero; D,E, F, R¹, R², R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, are as previously defined;

R₃ is the moiety ##STR33## wherein Ar is ##STR34## and R₆ is selectedfrom the group ##STR35## where Ar' is selected from the group ##STR36##and W', R_(a), R_(b) and cycloalkyl are as previously described.

More particularly preferred are compounds of the formulae: ##STR37##wherein the moiety: ##STR38## is selected from a phenyl, thiophene,furan, pyrrole or pyridine ring; R³ is the moiety: ##STR39## wherein Aris the moiety: ##STR40## R⁶ is ##STR41## and Ar' is selected from themoieties: ##STR42## wherein R_(a), R_(b), R⁵, R⁷, R⁸, R⁹, cycloalkyl andW' are as hereinbefore described;

R¹¹ is selected from hydrogen, halogen, (C₁ -C₃) lower alkyl, hydroxy,##STR43## --CHO, and (C₁ -C₃)lower alkoxy; and R¹² is selected fromhydrogen, (C₁ -C₃)lower alkyl, halogen and (C₁ -C₃)lower alkoxy.

Also particularly preferred are compounds of the formulae: ##STR44##wherein m is one or two; the moiety: ##STR45## is selected from aphenyl, thiophene, furan, pyrrole or pyridine ring; R³ is the moiety:##STR46## wherein Ar is the moiety: ##STR47## R⁶ is ##STR48## (CH₂)_(n)cycloalkyl; Ar' is selected from the moieties: ##STR49## wherein R_(a),R_(b), R⁵, R⁶, R⁸, R⁹, cycloalkyl and W' are as hereinbefore defined;

R¹¹ is selected from hydrogen, halogen, (C₁ -C₃) lower alkyl, hydroxy,##STR50## --CHO, and (C₁ -C₃)lower alkoxy; and R¹² is selected fromhydrogen, (C₁ -C₃)lower alkyl, halogen and (C₁ -C₃)lower alkoxy.

More particularly preferred are compounds of the formulae: ##STR51## R³is the moiety: ##STR52## wherein Ar is the moiety: ##STR53## R⁶ is##STR54## wherein cycloalkyl is defined as C₃ -C₆ cycloalkyl,cyclohexenyl or cyclopentenyl; R_(b) is hydrogen; R_(a) is independentlyselected from hydrogen, --CH₃, --C₂ H₅ or --(CH₂)_(q) N(CH₃)₂ ; Ar' isselected from the moieties: ##STR55## wherein q, R_(a), R_(b), R⁵, R⁷,R⁸, R⁹, R¹¹ and W' are as hereinbefore described;

R¹² and R¹³ are independently selected from hydrogen, (C₁ -C₃) loweralkyl, halogen, amino, (C₁ -C₃) lower alkoxy or (C₁ -C₃) loweralkylamino.

Also particularly preferred are compounds of the formulae: ##STR56##wherein m is one or two; R³ is the moiety: ##STR57## wherein Ar is themoiety: ##STR58## R⁶ is ##STR59## wherein cycloalkyl is defined as C₃-C₆ cycloalkyl, cyclohexenyl or cyclopentenyl; R_(b) is hydrogen;

R_(a) is independently selected from hydrogen, --CH₃, --C₂ H₅ or--(CH₂)_(q) N(CH₃)₂ ; and Ar' is selected from the moieties: ##STR60##wherein q, R⁵, R⁷, R⁸, R⁹, R¹¹ and W' are as hereinbefore defined;

R¹² and R¹³ are independently selected from hydrogen, (C₁ -C₃) loweralkyl, halogen, amino, (C₁ -C₃)lower alkoxy or (C₁ -C₃)lower alkylamino.

Among the more preferred compounds of this invention are those selectedfrom Formula I: ##STR61## wherein; A--B is ##STR62## wherein m is one ortwo; the moiety ##STR63## represents a fused phenyl or fused substitutedphenyl optionally substituted by one or two substituents selected from(C₁ -C₃) lower alkyl, halogen, amino, (C₁ -C₃) lower alkoxy, or (C₁ -C₃)lower alkylamino;

the moiety: ##STR64## is a five-membered aromatic (unsaturated) fusednitrogen-containing heterocyclic ring wherein D is carbon or nitrogen,and E, and F are carbon and wherein the carbon atoms may be optionallysubstituted by a substituent selected from halogen, (C₁ -C₃) loweralkyl, hydroxy, COCCl₃, COCF₃, ##STR65## --CHO, amino, (C₁ -C₃) loweralkoxy, (C₁ -C₃) lower alkylamino , CONH (C₁ -C₃) lower alkyl, or --CONlower alkyl (C₁ -C₃)!₂,

R_(b) is independently selected from H, --CH₃, or --C₂ H₅ ;

q is 1 or 2;

R₃ is the moiety ##STR66## wherein Ar is a moiety selected from thegroup ##STR67## and X is selected from O, S, NH, --NCH₃, or --N--COCH₃ ;R₄ is selected from H, lower alkyl (C₁ -C₃), --CO-lower alkyl (C₁ -C₃),SO₂ lower alkyl (C₁ -C₃), or the moieties of the formulae: ##STR68## R₁and R₂ are, independently, H, (C₁ -C₃) lower alkyl, (C₁ -C₃) loweralkoxy, or halogen;

R₅ is H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy or halogen;

R₆ is selected from:

(a) moieties of the formula: ##STR69## wherein cycloalkyl is defined asC₃ to C₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

n is 0-2;

R_(a) is independently selected from H, --CH₃, --C₂ H₅, ##STR70##--(CH₂)_(q) Olower alkyl (C₁ C₃), or --CH₂ CH₂ OH;

R_(b) is as hereinbefore defined;

q is 1 or 2;

(b) a moiety of the formula: ##STR71## where R₂ is as hereinbeforedefined; (c) a moiety of the formula: ##STR72## wherein J is R_(a),lower alkyl (C₁ -C₈) branched or unbranched, lower alkenyl (C₂ -C₈)branched or unbranched, --O-lower alkyl (C₁ -C₈) branched or unbranched,--O-lower alkenyl (C₂ -C₈) branched or unbranched, tetrahydrofuran,tetrahydrothiophene, or --CH₂ --K wherein K is halogen, (C₁ -C₃) loweralkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ringmoiety: ##STR73## wherein D, E, F and G are selected from carbon ornitrogen and wherein the carbon atoms may be optionally substituted withhalogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO,(C₁ -C₃) lower alkoxy, or --CO₂ -lower alkyl (C₁ -C₃); and

R_(a) and R_(b) are as hereinbefore defined;

(d) a moiety selected from those of the formulae: ##STR74## whereinR_(c) is selected from halogen, (C₁ -C₃) lower alkyl, --O-lower alkyl(C₁ -C₃), OH ##STR75## q is 1 or 2; R_(a) and R_(b) are as hereinbeforedefined; wherein Ar' is selected from the group: ##STR76## wherein W' isselected from O, S, NH, N-lower alkyl (C₁ -C₃), --NHCO-lower alkyl (C₁-C₃), or NSO₂ -lower alkyl (C₁ -C₃);

R⁷ is selected from H, lower alkyl (C₁ -C₃), halogen, --O-lower alkyl(C₁ -C₃), or CF₃ ;

R⁸ and R⁹ are independently selected from hydrogen, lower alkyl (C₁-C₃), S-lower alkyl (C₁ -C₃), halogen, --NH-lower alkyl (C₁ -C₃),--OCF₃, --CN, --OH, --S--CF₃, --NO₂, NH₂, or --O-lower alkyl (C₁ -C₃);

R¹⁰ is H, halogen, or lower alkyl-(C₁ -C₃);

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

Within the group above are the following preferred sub-groups 1 to 5 ofcompounds:

1. wherein R³ is the moiety: ##STR77## and Ar is the moiety ##STR78##wherein R⁵, R⁶, and R⁷ are as defined in claim 1 or a pharmaceuticallyacceptable salt, ester or pro-drug form thereof.

2. compounds of the formula: ##STR79## and Ar is the moiety ##STR80##wherein R⁵, R⁶, and R⁷ are as defined in claim 1 and Ar' is selectedfrom the moieties ##STR81## wherein R⁵, R⁸, R⁹ and W' are as defined inclaim 1, or a pharmaceutically acceptable salt, ester or pro-drug formthereof.

3. compounds of the formula: ##STR82## and Ar is the moiety ##STR83##wherein R⁵ and R⁷ are as defined in claim 1 and R⁶ is selected from:

(a) moieties of the formula: ##STR84## wherein cycloalkyl is defined asC₃ to C₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

n is 0-2;

R_(a) is independently selected from H, --CH₃, --C₂ H₅, ##STR85##--(CH₂)_(q) lower alkyl (C₁ C₃), or --CH₂ CH₂ OH;

q is 1 or 2;

R_(b) is selected from H, --CH₃, or C₂ H₅ ; or

(b) a moiety of the formula: ##STR86## wherein J is R_(a), lower alkyl(C₁ -C₈) branched or unbranched, lower alkenyl (C₂ -C₈) branched orunbranched, --O-lower alkyl (C₁ -C₈) branched or unbranched, --O-loweralkenyl (C₂ -C₈) branched or unbranched, tetrahydrofuran,tetrahydrothiophene, or --CH₂ --K wherein K is halogen, (C₁ -C₃) loweralkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ringmoiety: ##STR87## wherein D, E, F and G are selected from carbon ornitrogen and wherein the carbon atoms may be optionally substituted withhalogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO,(C₁ -C₃)lower alkoxy, or --CO₂ -lower alkyl (C₁ -C₃); and

R_(a) and R_(b) are as hereinbefore defined; or

(c) a moiety selected from those of the formulae: ##STR88## whereinR_(c) is selected from halogen, (C₁ -C₃) lower alkyl, --O-lower alkyl(C₁ -C₃), OH, ##STR89## q is 1 or 2; and R_(a) and R_(b) are ashereinbefore defined; wherein Ar' is selected from the group: ##STR90##wherein R⁸, R⁹ and W' are as defined in claim 1, or a pharmaceuticallyacceptable salt, ester or pro-drug form thereof.

4. compounds of the formula: ##STR91## wherein; A--B is ##STR92##wherein m is one; the moiety ##STR93## represents a fused phenyl orfused substituted phenyl optionally substituted by one or twosubstituents selected from (C₁ -C₃) lower alkyl, halogen, amino, (C₁-C₃) lower alkoxy, or (C₁ -C₃) lower alkylamino;

the moiety: ##STR94## is a five-membered aromatic (unsaturated) fusednitrogen-containing heterocyclic ring wherein D is carbon or nitrogen,and E, and F are carbon and wherein the carbon atoms may be optionallysubstituted by a substituent selected from halogen, (C₁ -C₃) loweralkyl, hydroxy, COCCl₃, COCF₃, ##STR95## --CHO, amino, (C₁ -C₃) loweralkoxy, (C₁ -C₃) lower alkylamino, CONH (C₁ -C₃) lower alkyl, or --CONlower alkyl (C₁ -C₃)!₂,

R_(b) is independently selected from H, --CH₃, or --C₂ H₅ ;

q is 1 or 2;

R₃ is the moiety ##STR96## wherein Ar is a moiety selected from thegroup ##STR97## and X is selected from O, S, NH, --NCH₃, or --N--COCH₃ ;R₄ is selected from H, lower alkyl (C₁ -C₃), --CO-lower alkyl (C₁ -C₃),SO₂ lower alkyl (C₁ -C₃), or the moieties of the formulae: ##STR98## R₁and R₂ are, independently, H, (C₁ -C₃) lower alkyl, (C₁ -C₃) loweralkoxy, or halogen;

R₅ is H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy or halogen;

R₆ is selected from:

(a) moieties of the formula: ##STR99## wherein cycloalkyl is defined asC₃ to C₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

n is 0-2;

R_(a) is independently selected from H, --CH₃, --C₂ H₅, ##STR100##--(CH₂)_(q) Olower alkyl (C₁ C₃), or --CH₂ CH₂ OH;

R_(b) is as hereinbefore defined;

q is 1 or 2;

(b) a moiety of the formula: ##STR101## where R₂ is as hereinbeforedefined; (c) a moiety of the formula: ##STR102## wherein J is R_(a),lower alkyl (C₁ -C₈) branched or unbranched, lower alkenyl (C₂ -C₈)branched or unbranched, --O-lower alkyl (C₁ -C₈) branched or unbranched,--O-lower alkenyl (C₂ -C₈) branched or unbranched, tetrahydrofuran,tetrahydrothiophene, or --CH₂ --K wherein K is halogen, (C₁ -C₃) loweralkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ringmoiety: ##STR103## wherein D, E, F and G are selected from carbon ornitrogen and wherein the carbon atoms may be optionally substituted withhalogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO,(C₁ -C₃)lower alkoxy, or --CO₂ -lower alkyl (C₁ -C₃); and

R_(a) and R_(b) are as hereinbefore defined;

(d) a moiety selected from those of the formulae: ##STR104## whereinR_(c) is selected from halogen, (C₁ -C₃) lower alkyl, --O-lower alkyl(C₁ -C₃), OH ##STR105## q is 1 or 2; R_(a) and R_(b) are as hereinbeforedefined; wherein Ar' is selected from the group: ##STR106## wherein W'is selected from O, S, NH, N-lower alkyl (C₁ -C₃), --NHCO-lower alkyl(C₁ -C₃), or NSO₂ -lower alkyl (C₁ -C₃);

R⁷ is selected from H, lower alkyl (C₁ -C₃), halogen, --O-lower alkyl(C₁ -C₃), or CF₃ ;

R⁸ and R⁹ are independently selected from hydrogen, lower alkyl (C₁-C₃), S-lower alkyl (C₁ -C₃), halogen, --NH-lower alkyl (C₁ -C₃),--OCF₃, --CN, --OH, --S--CF₃, --NO₂, NH₂, or --O-lower alkyl (C₁ -C₃);

R¹⁰ is H, halogen, or lower alkyl-(C₁ -C₃);

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

5. compounds of the formula: ##STR107## Formula I wherein;

A--B is ##STR108## wherein m is two; the moiety ##STR109## represents afused phenyl or fused substituted phenyl optionally substituted by oneor two substituents selected from (C₁ -C₃) lower alkyl, halogen, amino,(C₁ -C₃) lower alkoxy, or (C₁ -C₃) lower alkylamino;

the moiety: ##STR110## is a five-membered aromatic (unsaturated) fusednitrogen-containing heterocyclic ring wherein D is carbon or nitrogen,and E, and F are carbon and wherein the carbon atoms may be optionallysubstituted by a substituent selected from halogen, (C₁ -C₃) loweralkyl, hydroxy, COCCl₃, COCF₃, ##STR111## --CHO, amino, (C₁ -C₃) loweralkoxy, (C₁ -C₃) lower alkylamino, CONH (C₁ -C₃) lower alkyl, or --CONlower alkyl (C₁ -C₃)!₂,

R_(b) is independently selected from H, --CH₃, or --C₂ H₅ ;

q is 1 or 2;

R₃ is the moiety ##STR112## wherein Ar is a moiety selected from thegroup ##STR113## and X is selected from O, S, NH, --NCH₃, or --N--COCH₃; R₄ is selected from H, lower alkyl (C₁ -C₃), --CO-lower alkyl (C₁-C₃), SO₂ lower alkyl (C₁ -C₃), or the moieties of the formulae:##STR114## R₁ and R₂ are, independently, H, (C₁ -C₃) lower alkyl, (C₁-C₃) lower alkoxy, or halogen;

R₅ is H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy or halogen;

R₆ is selected from:

(a) moieties of the formula: ##STR115## wherein cycloalkyl is defined asC₃ to C₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

n is 0-2;

R_(a) is independently selected from H, --CH₃, --C₂ H₅, ##STR116##--(CH₂)_(q) Olower alkyl (C₁ C₃), or --CH₂ CH₂ OH;

R_(b) is as hereinbefore defined;

q is 1 or 2;

(b) a moiety of the formula: ##STR117## where R₂ is as hereinbeforedefined; (c) a moiety of the formula: ##STR118## wherein J is R_(a),lower alkyl (C₁ -C₈) branched or unbranched, lower alkenyl (C₂ -C₈)branched or unbranched, --O-lower alkyl (C₁ -C₈) branched or unbranched,--O-lower alkenyl (C₂ -C₈) branched or unbranched, tetrahydrofuran,tetrahydrothiophene, or --CH₂ --K wherein K is halogen, (C₁ -C₃) loweralkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ringmoiety: ##STR119## wherein D, E, F and G are selected from carbon ornitrogen and wherein the carbon atoms may be optionally substituted withhalogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO,(C₁ -C₃)lower alkoxy, or --CO₂ -lower alkyl (C₁ -C₃); and

R_(a) and R_(b) are as hereinbefore defined;

(d) a moiety selected from those of the formulae: ##STR120## whereinR_(c) is selected from halogen, (C₁ -C₃) lower alkyl, --O-lower alkyl(C₁ -C₃), OH ##STR121## q is 1 or 2; R_(a) and R_(b) are as hereinbeforedefined; wherein Ar' is selected from the group: ##STR122## wherein W'is selected from O, S, NH, N-lower alkyl (C₁ -C₃), --NHCO-lower alkyl(C₁ -C₃), or NSO₂ -lower alkyl (C₁ -C₃);

R⁷ is selected from H, lower alkyl (C₁ -C₃), halogen, --O-lower alkyl(C₁ -C₃), or CF₃ ;

R⁸ and R⁹ are independently selected from hydrogen, lower alkyl (C₁-C₃), S-lower alkyl (C₁ -C₃), halogen, --NH-lower alkyl (C₁ -C₃),--OCF₃, --CN, --OH, --S--CF₃, --NO₂, NH₂, or --O-lower alkyl (C₁ -C₃);

R¹⁰ is H, halogen, or lower alkyl-(C₁ -C₃);

and the pharmaceutically acceptable salts, esters and pro-drug formsthereof.

Among the more preferred compounds of this invention are those selectedfrom:

2-methyl-N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-chlorobenzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2,5-dichlorobenzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2,4-dichlorobenzamide.

N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-chloro-4-methylbenzamide.

N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-methyl-4-chlorobenzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2,4-dimethylbenzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2,3-dimethylbenzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-methoxybenzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-trifluoromethoxybenzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2,4-dimethoxybenzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2,6-dimethoxybenzamide.

N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2,6-dichlorobenzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2,6-dimethylbenzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-(methylthio)benzamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-methyl-3-thiophenecarboxamide.

N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-3-methyl-2-thiophenecarboxamide.

N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-methyl-3-furanecarboxamide.

N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-3-methyl-2-furanecarboxamide.

N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzeneacetamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-chlorobenzeneacetamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-methylbenzeneacetamide.

N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-methyl-3-thiopheneacetamide.

2-methyl-N- 4-(1-chloropyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide.

2-chloro-N- 4-(1-chloropyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide.

2,4-dichloro-N- 4-(1-chloropyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide.

2,5-dichloro-N- 4-(1-chloropyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide.

2,3-dimethyl-N- 4-(1-chloropyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide.

2,4-dimethyl-N- 4-(1-chloropyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide.

2,5-dimethyl-N- 4-(1-chloropyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methyl-5-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-chlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,5-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,4-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-chloro-4-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methyl-4-chlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,4-dimethylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,3-dimethylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methoxybenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-trifluoromethoxybenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,4-dimethoxybenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,6-dimethoxybenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,6-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,6-dimethylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methylthiobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methyl-3-thiophenecarboxamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-3-methyl-2-thiophenecarboxamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methyl-3-furanecarboxamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-3-methyl-2-furanecarboxamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!benzeneacetamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-chlorobenzeneacetamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methylbenzeneacetamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methyl-3-thiopheneacetamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2,5-dichlorophenyl!-2,3-dimethylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2,5-dichlorophenyl!-2-chlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2,5-dichlorophenyl!-2,4-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2,5-dichlorophenyl!-3,5-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2,5-dichlorophenyl!-2-methyl-4-chlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methoxybenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)-carbonyl!-3-chlorophenyl!-2-(trifluoromethoxy)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)car-bonyl!-3-chlorophenyl!-2-(trifluoromethyl)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,4-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-(methylthio)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-3-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-5-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-4-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)-carbonyl!-3-chlorophenyl!-4-fluoro-2-(trifluoromethyl)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)-carbonyl!-3-chlorophenyl!-2,3-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,3-difluorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)car-bonyl!-3-chlorophenyl!-2-fluoro-5-(trifluoromethyl)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)car-bonyl!-3-chlorophenyl!-2-fluoro-3-(trifluoromethyl)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)car-bonyl!-3-chlorophenyl!-4-fluoro-2-(trifluoromethyl)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,5-difluorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,3-difluorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,5-dimethylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-3-methyl-2-thiophenecarboxamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-thiophenecarboxamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-furanecarboxamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-3-methyl-2-furanecarboxamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-chlorobenzeneacetamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methylbenzeneacetamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-4-fluoro-3-(trifluoromethyl)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)car-bonyl!-2-chlorophenyl!-3-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,3-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,3-difluorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-4-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-5-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-fluoro-5-(trifluoromethyl)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-chlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,3-dimethylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,5-dimethylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-methoxybenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-(trifluoromethoxy)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-methoxy-4-chlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,6-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-(methylthio)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-(trifluoromethyl)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-3-(trifluoromethyl)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,3,5-trichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-3-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-5-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-4-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-2,4-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-2,3-dimethylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-3-fluoro-5-(trifluoromethyl)benzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-3-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-5-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-4-fluoro-2-methylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-2,4-dichlorobenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-2,3-dimethylbenzamide.

N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-3-fluoro-5-(trifluoromethyl)benzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)phenyl!-2-chloro-5-methylbenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)-2-chlorophenyl!-2-chloro-5-methylbenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)phenyl!-2-methyl-5-chlorobenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)-3-chlorophenyl!-2-methyl-5-chlorobenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)phenyl!-2-methyl-5-fluorobenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)-3-chlorophenyl!-2-methyl-5-fluorobenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)phenyl!-2-fluoro-5-methylbenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)-3-chlorophenyl!-2,5-dimethylbenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)-3-chlorophenyl!-2-methyl-6-fluorobenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)-3-chlorophenyl!-2-methyl-3-fluorobenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)-3-chlorophenyl!-2-chloro-6-fluorobenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)-3-chlorophenyl!-2-methoxybenzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)-3-chlorophenyl!-2-(trifluoromethyl)benzamide.

N- 4-(pyrazolo1,5-a!quinoxalin-5-ylcarbonyl)-3-chlorophenyl!-2-(trifluoromethoxy)benzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-fluorobenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3-chlorophenyl!-2-methyl-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3-chlorophenyl!-2,3-dimethylbenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3-chlorophenyl!-2,5-dimethylbenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3-chlorophenyl!-2,5-dichlorobenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chloro-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3-chlorophenyl!-2-fluoro-5-chlorobenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3-chlorophenyl!-2-chloro-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3-chlorophenyl!-2-cyanobenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3-chlorophenyl!-2-(methylthio)benzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!phenyl!-2-methoxybenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!phenyl!-2-methyl-5-fluorobenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!phenyl!-2,5-dimethylbenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!phenyl!-2-methyl-3-fluorobenzamide.

N- 4- (4,5-dihydro-6H-pyrazolo 1,5-a!1,5!benzodiazepin-6-yl)carbonyl!-3,6-dimethylphenyl!-2-methyl-5-fluorobenzamide.

Compounds of this invention may be prepared as shown in Scheme I byreaction of tricyclic derivatives of Formula 3a and 3b with asubstituted or unsubstituted 4-nitrobenzoyl chloride to give theintermediates 5a and 5b. Reduction of the nitro group in intermediates5a and 5b gives the 4-aminobenzoyl derivatives 6a and 6b. The reductionof the nitro group in intermediates 5a and 5b may be carried out undercatalytic reduction conditions (hydrogen-Pd/C; Pd/C-hydrazine-ethanol)or under chemical reduction conditions (SnCl₂ -ethanol; Zn-acetic acid;TiCl₃) and related reduction conditions known in the art for convertinga nitro group to an amino group. The conditions for conversion of thenitro group to the amino group are chosen on the basis of compatabilitywith the preservation of other functional groups in the molecule.

Reaction of compounds of Formula 6a and 6b with aroyl chloride orrelated activated aryl carboxylic acids in solvents such as chloroform,dichloromethane, dioxane, tetrahydrofuran, toluene and the like in thepresence of a tertiary base such as triethylamine anddiisopropylethylamine or pyridine and the like, affords the compounds 8aand 8b which are vasopressin antagonists. ##STR123##

Reaction of tricyclic derivatives of Formula 6a and 6b with either acarbamoyl derivative 9 or a isocyanate derivative 10 gives compounds(Scheme 2) of Formula 11a and 11b which are vasopressin antagonists ofFormula I wherein R⁶ is ##STR124##

Reaction of tricyclic derivatives of Formula 6a and 6b with arylaceticacids, activated as the acid chlorides 12, anhydrides, mixed anhydridesor activated with known activating reagents, gives compounds 13a and 13b(Scheme 3). ##STR125##

The compounds of Formula I wherein Y, A--B, Z, R¹, R² and R³ are asdefined and the Ar moiety of R³ (--COAr) is ##STR126## may be prepared,as shown in Scheme 4, by reacting an activated ester of theindole-5-carboxylic acids 14 with tricyclic derivatives 3a and 3b. Theindole-5-carboxylic acids 14 may be activated by preparing theanhydride, a mixed anhydride or reacting with diethyl cyanophosphonate,N,N-carbonyldiimidazole or related peptide coupling reagents. As anexample, the derivative 15 may be prepared by the acid 14 andN,N-carbonyldiimidazole in tetrahydrofuran; the solvent is removed andthe derivative reacted with 3a or 3b at 100° C. to 120° C. without asolvent. Alternatively, 3a and 3b may be reacted with 15 in a solventsuch as toluene or xylene at reflux temperatures. The activating reagentfor the indole acids 14 is chosen on the basis of its compatibility withthe R⁴ group and its reactivity with the tricyclic derivatives 3a and 3bto give the vasopressin antagonists 16a and 16b. ##STR127##

The compounds of Formula I wherein Y, A--B, Z, R¹, R² and R³ are asdefined and the Ar moiety of R³ (--COAr) is ##STR128## wherein R⁶ is##STR129## may be prepared as shown in Scheme 5 by first convertingderivatives 8a and 8b into the intermediates 17a and 17b and thenreacting these intermediates with sodium or lithium azide to give theproducts 18a and 18b. ##STR130##

Alternatively, the products 18a and 18b may be prepared by couplingtetrazole derivatives of the Formula 19 with tricyclic derivatives 3aand 3b (Scheme 6). The tetrazole carboxylic acids are activated forcoupling to the tricyclic compounds 3a and 3b by reaction with peptidecoupling reagents, by conversion to the acid chlorides, anhydrides ormixed anhydrides. ##STR131##

As an alternative method for synthesis of compounds of this invention asdepicted in Formula I wherein Y, A--B, D, E, F and Z are as previouslydescribed and R³ is ##STR132## is the coupling of aryl carboxylic acids20 with the tricyclic derivatives 3a and 3b to give 21a and 21b.

The aryl carboxylic acids are activated for coupling by conversion to anacid chloride, bromide or anhydride or by first reacting with anactivating reagent such as N,N-dicyclocarbodiimide, diethylcyanophosphonate and related "peptide type" activating reagents. Themethod of activating the acids 20 for coupling to the tricyclicderivatives 3a and 3b is chosen on the basis of compatibility with othersubstituent groups in the molecule. The method of choice is theconversion of the aryl carboxylic acids 20 to the corresponding aroylchloride. The aryl acid chlorides 22 may be prepared by standardprocedures known in the art, such as reaction with thionyl chloride,oxalyl chloride and the like. The coupling reaction is carried out insolvents such as halogenated hydrocarbons, toluene, xylene,tetrahydrofuran dioxane in the presence of pyridine or tertiary basessuch as triethylamine and the like (Scheme 7). Alternatively, the aroylchlorides 22, prepared from the aryl carboxylic acids 20, may be reactedwith derivatives 3a and 3b in pyridine with or without4-(dimethylamino)pyridine.

In general, when the aryl carboxylic acids 20 are activated withN,N-carbonyldiimidazole and other "peptide type" activating reagents,higher temperatures are required than when the aroyl chlorides are used.The reaction may be carried out in a higher boiling solvent xylene orwithout a solvent (100° C. to 150° C.). ##STR133##

The starting materials 3a and 3b in the foregoing Schemes 1-7 may beprepared as follows. In accordance with Scheme 8, alkylation ofheterocycles of structural type 24 with an alkylating moiety such as 23gives intermediates 25. The heterocycle 24 may contain ane-carboxaldehyde function or an α-carboxylic and/or ester function asshown in Scheme 8. Where the intermediate 25 (R¹⁵ ═H) contains anα-carboxaldehyde group, hydrogenation with palladium-on-carbon givesreduction and ring closure in one step to give 29.

In derivatives 25 where R¹⁵ is an α-carboxylic and/or an α-carboxylicester function, the intermediate amino acid derivative 27 is firstisolated and then ring closed. The ring closure of derivatives 27 may becarried out by heating or by activation of the acid function (27: R¹⁵═H) for ring closure. The cyclic lactams 28 are conveniently reducedwith diborane or lithium aluminum hydride to give intermediates 29.Reaction of tricyclic derivatives 29 with aroyl chlorides (ArCOCl),where Ar is as hereinbefore defined, gives diazepines 26.

Tricyclic derivatives of structural type 36 may be prepared as shown inScheme 9. Formylation of 32 under known conditions in the literature,such as Viismeier formylation, gives intermediates 35 which on reductionand ring closure affords tricyclics 37.

Where Z is a fused substituted or unsubstituted phenyl group, theprocedure gives pyrrolo 1,2-a!quinoxalines 36. These derivatives 36 and37 may be reacted with aroyl chlorides (ArCOCl) wherein Ar is aspreviously defined or with a substituted or unsubstituted 4-nitrobenzoylchloride or with a nitrogen protecting group, such as benzyloxycarbonylchloride to give compounds 38 and 39. The compounds 38 and 39 may bereacted with chlorine, bromine or halogenating reagents such asN-chlorosuccinimide, N-bromosuccinimide and the like to give compounds40 and 41 wherein R¹⁷ is a halogen atom. The derivatives 38 and 39 maybe formylated and acetylated to give products 40 and 41 wherein R¹⁷ is aCHO or a --COCH₃ group. Halogenation, formylation and acetylation ofderivatives 36 gives 1-substituted pyrrolo 1,2-a!quinoxalines. Thederivatives 38, 39, 40 and 41 wherein R¹⁶ is a substituted orunsubstituted 4-nitrobenzoyl group are reduced to give the4-aminobenzoyl derivatives 42d and 43d which are reacted with reagentsAr'COCl, Ar'CH₂ COCl or ##STR134## wherein Ar' and R_(b) are aspreviously hereinbefore defined, to give tricyclic diazepines 44 and 45.##STR135##

The compounds of this invention wherein R³ is the moiety: ##STR136## andthe Ar group is the moiety: ##STR137## and R⁶ is a ##STR138## group,wherein R_(a), R⁵, R⁷ and Ar' are as previously hereinbefore defined,are synthesized as shown in Scheme 10. The tricyclic derivatives 46 and47are reacted with the mono methyl terephthaloyl chloride 48 to give thearoylated methyl ester compounds 49 and 50. Hydrolysis of the methylesters 49 and 50 gives the acids 51 and 52 which are activated forcoupling by conversion to an activated ester or converted to the acidchlorides 53 and 54. Reaction of the acid chlorides 53 and 54 with theamines, ##STR139## wherein R_(a) and Ar' are as hereinbefore definedgives the derivatives 55 and 56. ##STR140##

Preparation of some tricyclic diazepines useful for starting materialsfor the synthesis of compounds of this invention are shown in Schemes 8and 9. Other tricyclic diazepines are prepared by literature proceduresor by methods known in the art or by procedures reported for thesynthesis of specific known tricyclic diazepines. These diazepine ringsystems discussed below when subjected to reaction conditions shown inSchemes 1, 2, 3, 4, 5, 6, 7, 9 and 10 give the compounds of thisinvention.

The tricyclic diazepine ring system, 10,11-dihydro-5H-imidazo 2,1-c!1,4!benzodiazepine, ##STR141## is reported by G. Stefancich, R.Silvestri and M. Artico, J. Het. Chem. 30, 529(1993); ring substitutionon the same ring system is reported by G. Stefancich, M. Artico, F.Carelli, R. Silvestri, G. deFeo, G. Mazzanti, I. Durando, M. Palmery, ILFarmaco, Ed. Sc., 40, 429(1985). ##STR142##

The synthesis of 9,10-dihydro-4H-furo 2,3-e!pyrrolo 1,2-a!1,4!diazepin-9-one ##STR143## is reported by F. Povazunec, B. Decroixand J. Morel, J. Het. Chem. 29, 1507(1992) and is reduced to give thetricyclic heterocycle 9,10-dihydro-4H-furo 2,3-e!pyrrolo 1,2-a!1,4!diazepine. ##STR144## The tricyclic 5,10-dihydro-4H-pyrazolo 5,1-c!1,4!benzodiazepine ring system is reported by L. Cecchi and G.Filacchioni, J. Het. Chem., 20, 871(1983); ##STR145## The synthesis of9-oxo-9,10-dihydro-4H-pyrrolo 1,2-a!thieno 2,3-e! 1,4!diazepine isreported by A. Daich and B. Decroix, Bull. Soc. Chim. Fr 12, 360(1992);##STR146## and is reduced with boron-dimethylsulfide to give9,10-dihydro-4H-pyrrolo 1,2-a!thieno 2,3-e! 1,4!diazepine. ##STR147##Also reported by A. Daich and B. Decroix is 5-oxo-4,5-dihydropyrrolo1,2-a!thieno 3,2-e! 1,4!diazepine ##STR148## which is also reduced togive 4,10-dihydro-5H-pyrrolo 1,2-a!thieno 3,2-e! 1,4!diazepine##STR149## Reported by B. Decroix and J. Morel, J. Het. Chem., 28,81(1991) are pyrrolo 1,2-a!thieno 3,2-e! 1,4!diazepine; ##STR150## andpyrrolo 1,2-a!thieno 2,3-e! 1,4!diazepine. Reduction by hydrogen-Pd/c orchemical reduction with reagents such as sodium cyanoborohydride andacetic acid gives the dihydro tricyclic heterocycles ##STR151## Thesynthesis of the tricyclic 1,5-benzodiazepine ring system,6,7-dihydro-5H-pyrrolo 1,2-a! 1,5!benzodiazepine, has been reported byF. Chimenti, S. Vomero, R. Giuliano and M. Artico, IL Farmaco, Ed. Sc.,32, 339(1977). Annelated 1,5-benzodiazepines containing five memberedrings have been reviewed by A. Chimirri, R. Gitto, S. Grasso, A. M.Monforte, G. Romeo and M. Zappala, Heterocycles, 36, No. 3, 604(1993),and the ring system 6,7-dihydro-5H-pyrrolo 1,2-a! 1,5!benzodiazepine isdescribed. ##STR152##

The preparation of 5,6-dihydro-4H- 1,2,4!triazolo 4,3-a!1,5!benzodiazepin-5-ones from1,2-dihydro-3H-4-dimethylamino-1,5-benzodiazepin-2-ones has beendescribed by M. DiBroccio, G. Roma, G. Grossi, M. Ghia, and F. MattioliEur. J. Med. Chem; 26, 489(1991). Reduction of 5,6-dihydro-4H-1,2,4!triazolo 4,3-a! 1,5!benzodiazepin-5-ones with diborane or lithiumhydride gives the tricyclic 5,6-dihydro derivatives. ##STR153##

The compounds of this invention and their preparation can be understoodfurther by the following examples, but should not constitute alimitation thereof.

EXAMPLE 1 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2,3-difluorobenzamide

To a stirred solution of 0.350 g of 2,3-difluorobenzoyl chloride in 5 mlof methylene chloride is added 0.346 ml of triethylamine. After stirringfor 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine is added and stirring continued for 72 hours.The reaction mixture is filtered and the solid washed with methylenechloride. The solid is saved. The combined filtrate is washed withwater, 2N citric acid, 1M NaHCO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered and evaporated in vacuo to give 100 mg of asolid. The two solids are combined and dried to afford 790 mg of thedesired product as a solid, m.p. 252°-258° C.

EXAMPLE 2 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-methoxybenzamide

To a stirred solution of 0.362 g of 2-methoxybenzoyl chloride 5 ml ofmethylene chloride is added 0.346 g of triethylamine at 0° C. Afterstirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added and stirring continued for 18 hours at room temperature. Thereaction mixture is diluted with 45 ml of methylene chloride and washedwith water, 2N citric acid, 1M NaHCO₃, and brine. The reaction mixtureis dried with Na₂ SO₄, filtered through hydrous magnesium silicate andevaporated in vacuo to give a solid which is purified by crystallizationfrom ethyl acetate to give 0.430 g of the desired product as acrystalline solid, m.p. 185°-188° C.

EXAMPLE 3 2-Methyl-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzamide

To a mixture of 1.93 g of 4- (2-methylbenzoyl)amino!benzoyl chloride in15 ml of methylene chloride, cooled to 0° C. is added 1.13 ml oftriethylamine. After stirring for 3 minutes, a mixture of 1.0 g of10,11-dihydro-5H-pyrrolo 2,1-c! 1,4!benzodiazepine in 5 ml of methylenechloride is added. The cooling bath is removed and after about 30minutes a complete solution is obtained. The reaction mixture is allowedto stir at room temperature for 48 hours and the volatiles areconcentrated in vacuo to a residue. The residue is dissolved in 100 mlof ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO₃and brine. The solution is dried with Na₂ SO₄ and the volatilesconcentrated in vacuo to give 3.0 g of a residue. A 300 mg sample of theresidue is purified by thick layer chromatography using 10% ethylacetate-methylene chloride to give 160 mg of the desired product. Theremainder of the crude material is purified by flash chromatographyusing 10% ethyl acetate in methylene chloride to give the desiredproduct as a residue which is crystallized from ethyl acetate to give800 mg of the desired product as white crystals, m.p. 212°-215° C.

EXAMPLE 4

N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2,5-dichlorobenzamide

To a solution of 414.5 mg of 2,5-dichlorobenzoyl chloride in 5 ml ofmethylene chloride is added 276 μl of triethylamine. After stirring at0° C. for 3 minutes 400 mg of the10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added. The bath is removed and the reaction mixture stirred at roomtemperature for 3 hours. The volatiles are concentrated in vacuo to givea residue which is dissolved in ethyl acetate and washed with water, 2Ncitric acid, 1M NaHCO₃ and brine. The organic layer is dried with Na₂SO₄ and concentrated in vacuo to a residue which is purified by thicklayer chromatography by elution with 1:1 ethyl acetate-hexanes to give aresidue. The residue is crystallized from ethyl acetate to give 220 mgof the desired product as white crystals, m.p. 218°-220° C.

EXAMPLE 5 N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-3-methyl-2-thiophenecarboxamide

To a solution of 318 mg of 3-methyl-2-thiophenecarbonyl chloride in 5 mlof methylene chloride at 0° C. is added 346 μl of triethylamine. Afterstirring for 3 minutes, 500 mg of the10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added. The bath is removed and the reaction mixture stirred at roomtemperature for 18 hours. The volatiles are concentrated in vacuo togive a residue which crystallizes from ethyl acetate to afford 800 mg ofsolid. The solid is dissolved in methylene chloride washed with water,2N citric acid, 1M NaHCO₃ and brine. The organic layer is filteredthrough hydrous magnesium silicate, dried with Na₂ SO₄ and concentratedin vacuo to give a residue which crystallizes from ethyl acetate toafford 400 mg of the desired product as a white solid, m.p. 232°-235° C.

EXAMPLE 6 N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2,4-dichlorobenzamide

To a solution of 415 mg of 2,4-dichlorobenzoyl chloride in 5 ml ofmethylene chloride at 0° C. is added 346 μl of triethylamine. Afterstirring for 3 minutes, 500 mg of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added. The bath is removed and the reaction mixture stirred at roomtemperature for 18 hours. The volatiles are concentrated in vacuo togive a residue which is dissolved in ethyl acetate, washed with water,2N citric acid, 1M NaHCO₃ and brine. The organic layer is dried with Na₂SO₄, filtered and concentrated in vacuo to give a residue which iscrystallized from ethyl acetate to give 420 mg of the desired product asa crystalline solid, m.p., 210°-212° C.

EXAMPLE 7 N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-chlorobenzamide

To a solution of 347 mg of 2-chlorobenzoyl chloride in 5 ml of methylenechloride at 0° C. is added 346 μl of triethylamineo After stirring for 3minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine is added. The bath is removed and the reactionmixture stirred at room temperature for 18 hours. The volatiles areconcentrated in vacuo to give a residue which is dissolved in methylenechloride, washed with water, 2N citric acid, 1M NaHCO₃ and brine. Theorganic layer is dried with Na₂ SO₄, filtered and concentrated in vacuoto give a residue which is crystallized from methylene chloride to give525 mg of the desired product as a white crystalline solid, m.p.228°-230° C.

EXAMPLE 8 N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-fluorobenzamide

To a solution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylenechloride at 0° C. is added 346 μl of triethylamine. After stirring for 3minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine is added. The bath is removed and the reactionmixture stirred at room temperature for 18 hours. The volatiles areconcentrated in vacuo to give a residue which is dissolved in methylenechloride, washed with water, 2N citric acid, 1M NaHCO₃ and brine. Theorganic layer is dried with Na₂ SO₄, filtered and concentrated in vacuoto give 620 mg of the desired product as a crystalline solid, m.p.257°-260° C.

EXAMPLE 9 2-Chloro-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide

A mixture of 0.273 g of 2-chlorophenylacetic acid is stirred at roomtemperature for 2 hours. The volatiles are evaporated in vacuo to aresidue which is distilled with toluene several times. The residue isdissolved in 10 ml of methylene chloride containing 0.26 ml oftriethylamine and while stirring 0.485 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineadded. The reaction mixture is stirred at room temperature for 18 hours.The volatiles are removed and the residue dissolved in ethyl acetatewhich is washed with water, 1N HCl, 1M NaHCO₃ and brine. The organiclayer is dried and evaporated to a residue which is purified by flashchromatography using 1:1 ethyl acetate-hexane to give the desiredproduct as a yellow solid, m.p. 99°-103° C.

EXAMPLE 10 1-(2-Nitrophenyl)-1H-pyrrole-2-carboxaldehyde

To a solution of 3.76 g of 1-(2-nitrophenyl)pyrrole in 20 ml ofN,N-dimethylformamide at 0° C. is added dropwise with stirring 3 ml ofphosphorus oxychloride. Stirring is continued for 30 minutes and thereaction mixture is heated at 90° C. for 1 hour. After cooling to roomtemperature the mixture is treated with crushed ice and the pH adjustedto 12 with 2N sodium hydroxide. The resulting suspension is filtered,washed with water and dried to give 5.81 g of the desired product as alight yellow solid m.p. 119°-122° C.

EXAMPLE 11 4,5-Dihydro-pyrrolo- 1,2-a!-quinoxaline

To a solution of 1.0 g of 1-(2-nitrophenyl)-1H-pyrrole-2-carboxaldehydein 40 ml of ethyl alcohol and 40 ml of ethyl acetate, under argon, isadded 40 mg of 10% Pd/C. The mixture is hydrogenated at 40 psi for 2hours and filtered through diatomaceous earth. The filtrate isconcentrated in vacuo to a residue which is dissolved in ether andtreated with hexanes to give 0.35 g of the desired product as a beigesolid m.p. 108°-110° C.

EXAMPLE 12 4- (2-Methylbenzoyl)amino!benzoic acid

A mixture of 43.42 g of ethyl 4-aminobenzoate and 40.8 g of2-methylbenzoyl chloride in 150 ml of dichloromethane is cooled in anice bath and 26.56 g of triethylamine the solution is stirrer theaddition, the solution is stirred at room temperature overnight. Themixture is poured into water and the organic layer separated. Theorganic layer is washed with water, 1N HCl, 1M NaHCO₃ and dried over Na₂SO₄. The solvent is removed and the solid slurried with ethyl acetateand filtered to give 57 g of ethyl 4- (2-methylbenzoyl)amino!benzoate ascrystals, m.p. 110°-115° C. A mixture of 50.7 g of the precedingcompound in 280 ml of ethyl alcohol and 55 ml of 10N NaOH is refluxedfor 5 minutes. The mixture is cooled to room temperature, diluted with200 ml of water and acidified with concentrated hydrochloric acid (pH1-2). The mixture is filtered and the solid washed with water and driedto give 51 g of the desired product as white crystals, m.p. 270°-275° C.

EXAMPLE 13 4- (2-Methylbenzoyl)amino!benzoyl chloride

A mixture of 10.3 g of 4- (2-methylbenzoyl)amino!benzoic acid and 32 mlof thionyl chloride is refluxed for 1.5 hours. The solution isconcentrated in vacuo. Toluene is added and the solvent removed invacuo. Toluene is added and the mixture chilled and filtered to give thedesired product as a yellow solid, 135°-141° C.

EXAMPLE 14 2-Methyl-N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide

A mixture of 0.51 g of 4- (2-methylbenzoyl)amino!benzoyl chloride and0.36 g of 1,1'-carbonyldiimidazole in 6 ml of tetrahydrofuran is stirredat room temperature for 1 hour. To the reaction mixture is added 0.17 gof 4,5-dihydropyrrolo- 1,2-a!-quinoxaline followed by heating at refluxfor 60 hours. The volatiles are concentrated in vacuo to a residue whichis dissolved in ethyl acetate. The organic layer is washed with 1N HCl,1M NaHCO₃, brine, dried with Na₂ SO₄ and filtered through hydrousmagnesium silicate. The volatiles are concentrated in vacuo to a residuewhich is chromatographed by elution with 1:2 ethyl acetate-hexanes togive 0.14 g of the desired product as a white solid, m.p. 206°-207° C.;

MASS SPEC (CI) 408(MH⁺).

                  TABLE 1                                                         ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 14 with the                                         appropriateiy substituted aroyl chloride                                      Example                                                                       No.          Compound                                                         ______________________________________                                        15           N- 4-(pyrrolo 1,2-a!quinoxalin-                                               5(4H)-ylcarbonyl)phenyl!-2-                                                   chlorobenzamide                                                  16           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2,5-dichloro-                                              benzamide                                                        17           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2,4-dichloro-                                              benzamide, m.p. 200°-202° C.                       18           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2-chloro-4-methyl-                                         benzamide                                                        19           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2-methyl-4-chloro-                                         benzamide                                                        20           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2,4-dimethyl-                                              benzamide                                                        21           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2,3-dimethyl-                                              benzamide, m.p. 216-220° C.                               22           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2-methoxy-                                                 benzamide                                                        23           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2-trifluoro-                                               methoxybenzamide                                                 24           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2,4-dimethoxy-                                             benzamide                                                        25           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!2,6-dimethoxy-                                              benzamide                                                        26           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!benzamide                                      27           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2,6-dichloro-                                              benzamide                                                        28           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2,6-dimethyl-                                              benzamide                                                        29           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2-(methylthio)-                                            benzamide                                                        30           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2-methyl-3-                                                benzamide                                                        31           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-3-methyl-2-                                                thiophenecarboxamide                                             32           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2-methyl-3-                                                furanecarboxamide                                                33           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-3-methyl-2-                                                furanecarboxamide                                                34           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!benzeneacetamide                               35           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2-chlorobenzene-                                           acetamide                                                        36           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2-methylbenzene-                                           acetamide (yellow foam); Anal. Calc'd                                         for C.sub.27 H.sub.23 N.sub.3 O.sub.2 : C, 76.9; H, 5.5; N,                   10.0; Found: C, 75.6; H, 6.0; N, 9.4                             37           N- 4-(pyrrolo 1,2-a!quinoxalin-5(4H)-                                         ylcarbonyl)phenyl!-2-methyl-3-                                                thiopheneacetamide                                               ______________________________________                                    

EXAMPLE 38 N-(2-Nitrobenzoyl)pyrrole-2-carboxaldehyde

To an ice bath cooled solution of 5.6 g of 2-pyrrolecarboxaldehyde in 40ml of tetrahydrofuran is added 2.4 g of 60% sodium hydride in mineraloil. The temperature elevates to 40° C. After stirring for 20 minutes asolution of 11.0 g of 2-nitrobenzoyl chloride in 20 ml oftetrahydrofuran is added dropwise over 20 minutes. After stirring in thecold for 45 minutes, the reaction mixture is poured into ice water andether then filtered. The cake is washed with additional ether. The twophase filtrate is separate and the ether layer dried and concentrated invacuo to give 10 g of a residue as a dark syrup which is scratched withethanol to give crystals which are collected by filtration, washed withether and then dried to afford 3.2 g of solid, m.p. 95°-99° C.

EXAMPLE 39 10,11-Dihydro-5H-pyrrolo 2,1-c! 1,4!benzodiazepin-5-one

A mixture of 1.5 g of N-(2-nitrobenzoyl)pyrrole-2-carboxaldehyde in 50ml of ethyl acetate, 2 drops of concentrated HCl and 0.3 g of 10% Pd/Cis shaken in a Parr apparatus under hydrogen pressure for 1.75 hours.The mixture is filtered, 0.4 g of 10% Pd/C added and the mixture shakenin a Parr apparatus under hydrogen pressure for 2 hours. The reactionmixture is filtered through diatomaceous earth and the filtrateconcentrated in vacuo to give 1.0 g of a yellow oil. The residue ispurified on thick layer chromatography plates by elution with 4:1 ethylacetate:hexane to give 107 mg of the desired product as an oily solid.

EXAMPLE 40 2-Methyl-N- 4- (5-oxo-5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl)carbonyl!phenyl!benzamide

To a stirred solution of 107 mg of 10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepin-5-one in 3 ml of methylene chloride containing 0.084ml of triethylamine is added 165 mg of 4- (2-methylbenzoyl)amino!benzoylchloride and stirring continued for 6 hours. The volatiles are removedin vacuo to a residue which is purified on thick layer chromatographyplates with 7:3 hexane-ethyl acetate to afford the desired product as afoam.

EXAMPLE 41 N- 4-(3-Chloro-5H-pyrrolo 2,1-c!1,4!benzodiazepine-10(11H)ylcarbonyl)phenyl!-2-methylbenzamide

To an ice-water cooled suspension of 211 mg of 2-methyl-N- 4-(5H-pyrrolo2,1-c! 1,4!-benzodiazepin-10(11H)-ylcarbonyl)-phenyl!benzamide in 5 mlof tetrahydrofuran is added 67 mg of N-chlorosuccinimide followed bycontinued stirring in the cold for 10 minutes. The bath is removed andstirring continued for 2.25 hours. The reaction mixture is added toice-water and extracted with ether. The organic layer is dried andconcentrated in vacuo to give a foam which is crystallized from ethylacetate-hexane to give 157 mg of the desired product as an orange-pinksolid, m.p. 185°-187° C.

EXAMPLE 42 2-Methyl-N- 4-(1-chloropyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!benzamide

To an ice-water cooled suspension of 5 mmol of 2-methyl-N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)-phenyl!benzamide in 5 ml oftetrahydrofuran is added 5.5 mmol of N-chlorosuccinimide followed bycontinued stirring in the cold for 10 minutes. The bath is removed andstirring continued for 2.25 hours. The reaction mixture is added toice-water and extracted with ether. The organic layer is dried andconcentrated in vacuo to give the desired product as a solid.

                  TABLE II                                                        ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 42.                                                 Example                                                                       No.            Compound                                                       ______________________________________                                        43             2-chloro-N- 4-(1-chloropyrrolo-                                                1,2-a!quinoxalin-                                                            5(4H)-ylcarbonyl)phenyhl!-                                                    benzamide                                                      44             2,4-dichloro-N- 4-(1-chloro-                                                  pyrrolo- 1,2-a!quinoxalin-                                                    5(4H)-ylcarbonyl)phenyl!-                                                     benzamide                                                      45             2,4-dichloro-N- 4-(1-chloro-                                                  pyrrolo- 1,2-a!quinoxalin-                                                    5(4H)-ylcarbonyl)phenyl!-                                                     benzamide                                                      46             2,3-dimethyl-N- 4-(1-chloro-                                                  pyrrolo- 1,2-a!quinoxalin-                                                    5(4H)-ylcarbonyl)phenyl!-                                                     benzamide                                                      47             2,4-dimethyl-N- 4-(1-chloro-                                                  pyrrolo- 1,2-a!quinoxalin-                                                    5(4H)-ylcarbonyl)phenyl!-                                                     benzamide                                                      48             2,5-dimethyl-N- 4-(1-chloro-                                                  pyrrolo- 1,2-a!quinoxalin-                                                    5(4H)-ylcarbonyl)phenyl!-                                                     benzamide                                                      ______________________________________                                    

EXAMPLE 49 3-Chloro-10,11-dihydro-10-(4-nitrobenzoyl-5H-pyrrolo 2,1-c!1,4!-benzodiazepine

To an ice-water cooled solution of 250 mg of10,11-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepine in6 ml of tetrahydrofuran is added mg of N-chlorosuccinimide. The reactionmixture is stirred in the cold for 30 minutes and at room temperaturefor 2 hours. The reaction mixture is poured into ice water, stirred for5 minutes and extracted with ether. The organic layer is dried andconcentrated in vacuo to give 0.2 g of a yellow foam. Trituration withethyl alcohol gives 66 mg of the desired product as a yellow solid, m.p.119°-125° C.

EXAMPLE 50 3-Chloro-10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine

A mixture of 1 mmol of3-chloro-10,11-dihydro-10-(4-nitroaminobenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 2.5 mmol of anhydrous hydrazine, 50 mg of palladiumon carbon and 10 ml of ethyl alcohol is refluxed for 1.5 hours. Themixture is filtered through diatomaceous earth and the filtrateconcentrated to dryness to give the desired product as a solid.

EXAMPLE 51 N- 4-(3-Chloro-5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)ylcarbonyl)phenyl!-2-methylbenzamide

A mixture of 1 mmol of3-chloro-10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 2 mmol of triethylamine, and 1.1 mmol of2-methylbenzoylchloride in 8 ml of dichloromethane is stirred at roomtemperature overnight. The mixture is washed with water, and 1M NaHCO₃and dried(Na₂ SO₄). The solvent is removed in vacuo to give a solidwhich is recrystallized from dichloromethane-hexane to give crystals,185°-187° C.

                  TABLE III                                                       ______________________________________                                        The following Examples are prepared using                                     the conditions of Examples 51 with the                                        appropriately substituted aroyl chloride                                      Example                                                                       No.          Compound                                                         ______________________________________                                        52           N- 4-(3-Chloro-5H-pyrrolo 1,2-c!                                               1,4!benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl!-2-chlorobenzamide                               53           N- 4-(3-Chloor-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl!-2,5-dichloro-                                                benzamide                                                        54           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazepin-10(11H)yl-                                                 carbonyl)phenyl!-2,4-dichloro-                                                benzamide (solid foam), Anal.                                                 Calc'd for C.sub.26 H.sub.14 Cl.sub.3 N.sub.3 O.sub.2 : C,                    61.1;                                                                         H, 3.6; N, 8.2; Cl, 20.8; Found:                                              C, 60.0; H, 3.5; N, 7.7; Cl, 20.3                                55           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-fluoro-                                                    benzamide                                                        56           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-chloro-4-                                                  methylbenzamide                                                  57           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-methyl-4-                                                  chlorobenzamide                                                  58           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2,4-dimethyl-                                                benzamide                                                        59           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2,3-dimethyl-                                                benzamide                                                        60           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-methoxy-                                                   benzamide                                                        61           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-trifluoro-                                                 methoxybenzamide                                                 62           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2,4-dimethoxy-                                               benzamide                                                        63           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2,6-dimethoxy-                                               benzamide                                                        64           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!benzamide                                        65           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2,6-dichloro-                                                benzamide                                                        66           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2,6-dimethyl-                                                benzamide                                                        67           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-methylthio-                                                benzamide                                                        68           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-methyl-3-                                                  thiophenecarboxamide                                             69           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-3-methyl-2-                                                  thiophenecarboxamide                                             70           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-methyl-3-                                                  furanecarboxamide                                                71           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-3-methyl-2-                                                  furanecarboxamide                                                72           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!phenylacetamide                                  73           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-chlorophenyl-                                              acetamide                                                        74           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-methylbenzene-                                             acetamide                                                        75           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-methyl-3-                                                  thiopheneacetamide                                               76           N- 4-(3-Chloro-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazapin-10(11H)yl-                                                 carbonyl)phenyl!-2-methyl-3-                                                  furanacetamide                                                   ______________________________________                                    

EXAMPLE 77 1-(2-Nitrobenzyl)-2-pyrrolecarboxaldehyde

To 5.56 g of 60% sodium hydride in mineral oil, washed three times withhexane, is added 300 ml of N,N-dimethylformamide under argon. Thereaction mixture is cooled in an ice-bath and 13.2 g ofpyrrole-2-carboxaldehyde is added slowly. The reaction mixture becomes acomplete solution and is stirred for an additional 10 minutes. Whilestirring, 30.0 g of 2-nitrobenzyl bromide is added slowly. Aftercomplete addition, the reaction mixture is stirred for 30 minutes, theice bath is removed and the reaction mixture stirred at room temperaturefor 24 hours. The N,N-dimethylformamide is concentrated in vacuo to givea residue which is stirred with ice water for 1 hour. The resultingsolid is collected, air dried, then vacuum dried to give 30.64 g of thedesired product as a tan solid, m.p. 128°-132° C.

EXAMPLE 78 10,11-dihydro-5H-pyrrolo 2,1-c! 1,4!benzodiazepine

A mixture of 30.6 g of 1-(2-nitrobenzyl)-2-pyrrolecarboxaldehyde and3.06 g of 10% Pd/C in 400 ml of ethyl acetate and 400 ml of ethylalcohol is hydrogenated over 18 hours. The reaction mixture is filteredthrough diatomaceous earth and the filtrate is treated with activatedcarbon and filtered through diatomaceous earth. The filtrate isconcentrated in vacuo to give a residue which is dissolved in methylenechloride containing ethyl alcohol. The solution is passed through a padof silica gel and the pad washed with a 7:1 hexane-ethyl acetatesolution to give 16.31 g of the desired product as solid, m.p. 145°-148°C.

EXAMPLE 79 10,11-Dihydro-10(4-nitrobenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine

To a solution of 3.3 g of 10,11-dihydro-5H-yrrolo 2,1-c!1,4!benzodiazepine in 50 ml of methylene chloride under argon is added5.0 ml of triethylamine followed by ice bath cooling. A solution of 4.0g of 4-nitrobenzoyl chloride in 20 ml of methylene chloride is addeddropwise. Following complete addition, the ice bath is removed and thereaction mixture stirred at room temperature for 2 hours. The volatilesare removed in vacuo to give a residue which is dissolved in ethylacetate. The solution is washed with water, 1N HCl, NaHCO₃, brine, driedwith Na₂ SO₄ and filtered. The filtrate is concentrated in vacuo to asolid which is dissolved in methylene chloride, passed through silicagel and the pad washed with ethyl acetate. The combined filtrate isconcentrated in vacuo to give 5.3 g of the desired product as a yellowsolid, m.p. 188°-190° C.

EXAMPLE 80 10,11-Dihydro-10-(4-aminobenzoyl!-5H-pyrrolo 2,1-c!1,4!benzodiazepine

A mixture of 2.00 g of 10,11-dihydro-10(4-itrobenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine in 15 ml of ethyl alcohol and 15 ml of ethyl acetatecontaining 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reactionmixture is filtered through a pad of diatomaceous earth. The filtrate isconcentrated in vacuo to a solid which is dissolved in methylenechloride, passed through silica gel and the pad washed with 3:1 ethylacetate-hexane. The filtrate is concentrated in vacuo to give 1.5 g ofthe desired product as a yellow solid, m.p. 166°-168° C.

EXAMPLE 81 10,11-Dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine

To a solution of 21.58 g of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine in 325 ml of ethyl alcohol is added 2.15 g of10% Pd/C and 5.16 g of hydrazine followed by stirring and heating underreflux for 15 hours. The room temperature reaction mixture is filteredthrough diatomaceous earth. The filtrate is concentrated in vacuo to asolid which is dissolved in methylene chloride and passed through a padof hydrous magnesium silicate. The filtrate is concentrated in vacuo togive 19.2 g of the desired product as a tan solid. The solid is purifiedby flash chromatography using 7:1 ethyl acetate-hexane to give 17.97 gof the desired product, m.p. 166°-168° C.

EXAMPLE 82 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-3-chlorobenzob!thiophene-2-carboxamide

To a stirred solution of 0.440 g of 3-chlorobenzo b!thiophen-2-carbonylchloride in 10 ml of methylene chloride is added 0.33 ml oftriethylamine. After stirring for 15 minutes, 0.485 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added and stirring continued for 18 hours. The reaction mixture iswashed with water, 1N HCl, NaHCO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography using 1:1 ethyl acetate-hexaneto give 0.49 g of solid, m.p. 220°-222° C.

EXAMPLE 83 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2,3-dimethylbenzamide

To a stirred solution of 0.320 g of 2,3-dimethylbenzoyl chloride in 10ml of methylene chloride is added 0.33 ml of triethylamine. Afterstirring for 15 minutes, 0.485 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added and stirring continued for 5 hours. The reaction mixture iswashed with water, 1N HCl, NaHCO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography using 1:1 ethyl acetate-hexaneto give 0.39 g of solid, m.p. 168°-170° C.

EXAMPLE 84 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-ethoxybenzamide

To a stirred solution of 0.362 g of 2-ethoxybenzoyl chloride 5 ml ofmethylene chloride is added 0.346 g of triethylamine at 0° C. Afterstirring for 3 minutes, 0,500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added and stirring continued for 72 hours at room temperature. Thereaction mixture is diluted with 45 ml of methylene chloride and washedwith water, 2N citric acid, NaHCO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography using 1:1 ethyl acetate-hexaneto give 0.890 g of solid which is crystallized from ethyl acetate togive 0.540 g of the desired product as a white solid, m.p. 160°-176° C.

EXAMPLE 85 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-(methylthio)benzamide

To a stirred solution of 0,364 g of 2-(methylthio)benzoyl chloride 5 mlof methylene chloride is added 0.346 g of triethylamine at 0° C. Afterstirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added and stirring continued for 72 hours at room temperature. Thereaction mixture is diluted with 45 ml of methylene chloride and washedwith water, 2N citric acid, NaHCO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography using 1:1 ethyl acetate-hexaneto give a solid which is crystallized from ethyl alcohol to give 0.480 gof the desired product as a white solid, m.p. 171°-174° C.

EXAMPLE 86 3-Methylbenzo b!thiophene-2-acetyl chloride

A mixture of 2.0 g of 3-methylbenzo b!thiophene-2-acetic acid and 19.4ml of thionyl chloride is heated at reflux for 1 hour. The volatiles areevaporated in vacuo to give a residue which is concentrated from toluenethree times and dried under vacuum to give 2.25 g of the desired productas a residue.

EXAMPLE 87 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-3-methylbenzob!thiophene-2-acetamide

To a stirred solution of 0.445 g of 3-methylbenzo b!thiophene-2-acetylchloride in 5 ml of methylene chloride is added 0.346 g of triethylamineat 0° C. After stirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added and stirring continued for 72 hours at room temperature. Anadditional 0.445 g of 3-methylbenzo b!thiophene-2-acetyl chloride, 0.346g of triethylamine and 30 mg of dimethylaminopyridine is added andstirring continued for an additional 18 hours. The reaction mixture isdiluted with 45 ml of methylene chloride and washed with water, 2Ncitric acid, 1M NaHCO₃, and brine. The reaction mixture is dried withNa₂ SO₄, filtered and evaporated in vacuo to give a solid which ispurified by flash chromatography using 1:1 ethyl acetate-hexane to give0.320 g of the desired product as a yellow foam.

EXAMPLE 88 4-Chloro-2-methoxybenzoyl chloride

A solution of 2.0 g of 4-chloro-o-anisic acid in 22 ml of thionylchloride is heated at reflux for 1 hour. The volatiles are evaporated invacuo to give a residue which is concentrated from toluene three timesand dried under vacuum to give 2.0 g of the desired product as aresidue.

EXAMPLE 89 N- 4-(5H-Pyrrolo 2,1-c!1,4!-benzodiazepin-10(11H)ylcarbonyl)phenyl!-4-chloro-2-methoxybenzamide

To a stirred solution of 0.406 g of 4-chloro-2-methoxybenzoyl chloridein 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C.After stirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added and stirring continued for 18 hours at room temperature. Anadditional 0.406 g of 4-chloro-2-methoxybenzoyl chloride and 0.346 g oftriethylamine is added and stirring is continued for 2 hours. Thereaction mixture is diluted with 45 ml of methylene chloride and washedwith water, 2N citric acid, 1M NaHCO₃, and brine. The reaction mixtureis dried with Na₂ SO₄, filtered and evaporated in vacuo to give aresidue which is purified by flash chromatography using 1:1 ethylacetate-hexane to give a solid which is crystallized from ethyl acetateto give 0.320 g of the desired product as a white crystals, m.p.222°-224° C.

EXAMPLE 90 2-(Trifluoromethyl)benzoyl chloride

A solution of 2.0 g of o-trifluoromethylbenzoic acid in 21 ml of thionylchloride is heated at reflux for 1 hour. The volatiles are evaporated invacuo to give a residue which is concentrated from toluene three timesand dried under vacuum to give 2.1 g of the desired product as aresidue.

EXAMPLE 91 N- 4-(5H-Pyrrolo2,1-c!!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-(trifluoromethyl)benzamide

To a stirred solution of 0.413 g of 2-trifluoromethylbenzoyl chloride in5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C.After stirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added and stirring continued for 18 hours at room temperature. Thereaction mixture is diluted with 50 ml of ethyl acetate and washed withwater, 2N citric acid, NaHCO₃, and brine. The reaction mixture is driedwith Na₂ SO₄, filtered and evaporated in vacuo to give a solid which iscrystallized from ethyl acetate to afford 0.5 g of a solid which isdissolved in methylene chloride and passed through a pad of hydrousmagnesium silicate. The filtrate is evaporated in vacuo to give a solidwhich is crystallized from ethyl acetate to afford 0.210 g of thedesired product as a white crystals, m.p. 226°-228° C.

EXAMPLE 92 2-Methylphenylacetyl chloride

A solution of 2.0 g of c-tolylacetic acid in 27 ml of thionyl chlorideis heated at reflux for 1 hour. The volatiles are evaporated in vacuo togive a residue which is concentrated from toluene three times and driedunder vacuum to give 2.1 g of the desired product as a light brown oil.

EXAMPLE 93 N- 4(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-methylbenzeneacetamide

To a stirred solution of 0.334 g of 2-methylphenylacetyl chloride 5 mlof methylene chloride is added 0.346 g of triethylamine at 0° C. Afterstirring for 3 minutes, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis added and stirring continued for 72 hours at room temperature. Thereaction mixture is diluted with 45 ml of methylene chloride and washedwith water, 2N citric acid, NaHCO₃, and brine. The reaction mixture isdried with Na₂ SO₄, filtered through a pad of hydrous magnesium silicateand evaporated in vacuo to give a solid which is purified by flashchromatography using 1:1 ethyl acetate-hexane to give a solid which iscrystallized from ethyl acetate to give 0.385 g of the desired productas white crystals, m.p. 198°-200° C.

EXAMPLE 94 10,11-Dihydro-10-(3-methyl-4-nitro-benzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine

A mixture of 1.81 g of 3-methyl-4-nitrobenzoic acid and 1.25 g ofthionyl chloride in 75 ml of chloroform is heated at reflux under argonfor 48 hours. The volatiles are removed in vacuo to a residue which isevaporated with toluene several times in vacuo. The residue is partiallydissolved in methylene chloride and filtered free of solids and thefiltrate evaporated in vacuo to give 1.47 g of the desired acidchloride. A 1.36 g sample of the acid chloride, 0.90 g ofN,N-diisopropylethylamine and 1.25 g of 10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine in 25 ml of methylene chloride is allowed to stand atroom temperature for 8 hours. Water is added to the reaction mixture,the organic layer is separated and dried over Na₂ SO₄, filtered andhexane added to the filtrate at the boil to give 1.4 g of the desiredproduct as crystals, m.p. 246°-248° C.

EXAMPLE 95 10,11-Dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine

A mixture of 1.22 g10,11-dihydro-10-(3-methyl-4-nitro-benzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 0.2 g of 10% Pd/C and 0.35 g of anhydrous hydrazinein 50 ml of absolute ethyl alcohol is heated on a steam bath for 1 hour.The reaction mixture is filtered hot through diatomaceous earth andevaporated in vacuo to a residue. The residue is crystallized frommethylene chloride-hexane to give 0.95 g of the desired product ascrystals, m.p. 232°-234° C.

EXAMPLE 96 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)-2-methylphenyl!-2-methylbenzamide

A solution of 0.83 g of10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 0.5 g of N,N-diisopropylethylamine and 0.6 g of2-methylbenzoyl chloride in 50 ml of methylene chloride is stirred atroom temperature for 18 hours. The reaction mixture is washed withwater, the organic layer dried with Na₂ SO₄ and passed through a pad ofhydrous magnesium silicate. Hexane is added at the boil to give 0.75 gof a solid which is crystallized from methylene chloride-hexane to give0.61 g of the desired product, m.p. 125°-130° C.

                  TABLE IV                                                        ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 96 with the                                         appropriately substituted aroyl chloride                                      Example                                                                       No.            Compound                                                       ______________________________________                                         97            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-2-                                                  chlorobenzamide                                                 98            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-2,-                                                 5-dichlorobenzamide                                             99            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2,4-dichlorobenzamide, m.p.                                                   213°-215° C.                                     100            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2-chloro-4-methylbenzamide                                     101            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2-methyl-4-chlorobenzamide                                     102            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2,3-dimethylbenzamide                                          103            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-2-                                                  methoxybenzamide                                               104            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-2-                                                  trifluoromethoxybenzamide                                      105            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-2,-                                                 4-dimethoxybenzamide                                           106            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    benzamide                                                      107            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2-methylthiobenzamide                                          108            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2,6-dichlorobenzamide                                          109            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2-methyl-3-thiophenecarbox-                                                   amide                                                          110            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2-methyl-3-thiophene-                                                         carboxamide                                                    111            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2-methyl-3-furancarboxamide                                    112            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    3-methyl-2-furancarboxamide                                    113            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    phenylacetamide                                                114            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2-chlorophenylacetamide                                        115            N- 4-(5H-pyrrolo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-yl-                                                     carbonyl)-2-methylphenyl!-                                                    2-methylphenylacetamide                                        ______________________________________                                    

EXAMPLE 116 10,11-Dihydro-10- 4-(2-methylphenyl!amino!carbonyl!amino!benzoyl!-5H-pyrrolo 2,1-c!1,4!benzodiazepine

A mixture of 0.93 g10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine and 0.37 g of o-tolyl isocyanate in 50 ml oftetrahydrofuran is heated at reflux under argon for 24 hours. Thevolatiles are evaporated in vacuo to a residue which is dissolved inmethylene chloride and passed through a pad of hydrous magnesiumsilicate. Hexane is added to the filtrate at the boil to give 0.68 g ofthe desired product as crystals, m.p. 155°-158° C.

EXAMPLE 117 N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-1H-indole-5-carboxamide

To a solution of 319 mg of indole-5-carboxylic acid in 5 ml oftetrahydrofuran is added 418.4 mg of 1,1'-carbonyldiimidazole underargon with ice-bath cooling. The cooling bath is removed and thereaction mixture stirred at room temperature for 2 hours. The volatilesare evaporated in vacuo to a residue which is dissolved in 3 ml ofxylene followed by 500 mg of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineand heating at 120° C. for 18 hours. The volatiles are evaporated invacuo to a residue which is partitioned between 40 ml of ethyl acetateand water. The organic layer is dried over Na₂ SO₄ and the volatilesevaporated in vacuo to a residue which is purified by chromatography onpreparative plates by elution with 1:1 ethyl acetate-hexane to give 140mg of the desired product as an orange solid, m.p. 130°-170° C.

EXAMPLE 118 1-(o-Nitrobenzyl)-imidazole-2-carboxaldehyde

A 2.0 g portion of sodium hydride (60% in oil) is washed with pentanetwo times. To the residue is added 110 ml of N,N-dimethylformamide underargon. With stirring and external cooling, 4.80 g of2-imidazolecarboxaldehyde is added and the cooling bath removed. Slightexternal heating results in a yellow solution. The reaction mixture ischilled in ice and 10.8 g of 2-nitrobenzyl bromide is added. Thereaction mixture is stirred at 0° C. for 18 hours. The volatiles areremoved in vacuo to a residue which is stirred with ice water, filteredand the cake washed well with water and suction dried to give 10.9 g ofthe desired product as a solid, m.p. 141°-144° C. MH+232.

EXAMPLE 119 10,11-Dihydro-5H-imidazo 2,1,c! 1,4!benzodiazepine

A 5.0 g sample of 1-(o-nitrobenzyl)-imidazole-2-carboxaldehyde isdissolved in 150 ml of hot ethyl alcohol, cooled to room temperature andfiltered. To the filtrate is added 0.5 g of 10% Pd/C and the mixturehydrogenated at 48 psi for 4 hours. An additional 0.5 g of 10% Pd/C isadded and hydrogenation continued for 25 hours at 65 psi. The mixture isfiltered through diatomaceous earth and the cake washed with ethylacetate. The filtrate is evaporated in vacuo to a residue which isdissolved in methylene chloride, treated with activated carbon, filteredthrough diatomaceous earth and hexanes added to the filtrate at the boilto give 1.86 g of the desired product as a crystalline solid, m.p.164°-170° C.

EXAMPLE 120 10,11-Dihydro-5H-imidazo 2,1-c! 1,4!benzodiazepine

To a suspension of 4 mmol of lithium aluminum hydride in 20 ml ofanhydrous tetrahydrofuran is added a 1 mmol solution of10,11-dihydro-11-oxo-5H-imidazo- 2,1-c! 1,4!benzodiazepine and themixture is refluxed for 24 hours and cooled at 0° C. To the mixture isadded dropwise 0.12 ml of water and 6 ml of 1N sodium hydroxide. Themixture is extracted with ethyl acetate and the solvent removed to givethe desired product as a solid. Recrystallization from methylenechloride-hexane gives crystals, m.p. 164°-170° C.

EXAMPLE 121 N- 4-(5H-imidazo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-methylbenzamide

To a mixture of 1.37 g (5 mmol) of 4- (2-methylbenzoyl)amino!benzoylchloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 mlof triethylamine. After stirring for 3 minutes, 5 mmol of10,11-dihydro-5H-imidazo 2,1-c! 1,4!benzodiazepine in 5 ml of methylenechloride is added. The cooling bath is removed and after about 30minutes a complete solution is obtained. The reaction mixture is allowedto stir at room temperature for 1 hour and the volatiles areconcentrated in vacuo. The residue is dissolved in 100 ml of ethylacetate and washed with water, 2N citric acid, and brine. The solutionis dried with Na₂ SO₄ and the volatiles concentrated in vacuo to givethe desired product as a solid.

EXAMPLE 122 10,11-Dihydro-10-(4-nitrobenzoyl)-5H-imidazo 2,1-c!1,4!benzodiazepine

To a solution of 10 mmol of 10,11-dihydro-5H-imidazo 2,1-c!1,4!benzodiazepine in 50 ml of methylene chloride under argon is added15 mmol of triethylamine followed by ice bath cooling. A solution of 10mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is addeddropwise. Following complete addition, the ice bath is removed and thereaction mixture stirred at room temperature for 2 hours. The volatilesare removed in vacuo to give a residue which is dissolved in ethylacetate. The solution is washed with water, and brine. The organic layeris dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solidwhich is purified by flash chromatography to give desired product as asolid.

EXAMPLE 123 10,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo 2,1-c!1,4!benzodiazepine

A mixture of 5 mmol of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo2,1-c! 1,4!benzodiazepine in 10 ml of ethyl alcohol and 10 ml of ethylacetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours in aParr hydrogenator at 35 psi of hydrogen. The reaction mixture isfiltered through a pad of diatomaceous earth. The filtrate isconcentrated in vacuo to a solid which is purified by flashchromatography to give the desired product.

EXAMPLE 124 10,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo 2,1-c!1,4!benzodiazepine

To a solution of 5 mmol of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo2,1-c! 1,4!benzodiazepine in 100 ml of ethyl alcohol is added 0.5 g of10% Pd/C and 10 mmol of hydrazine followed by stirring and heating underreflux for 3 hours. The reaction mixture is filtered throughdiatomaceous earth. The filtrate is concentrated in vacuo to a residuewhich is dissolved in methylene chloride and passed through a pad ofhydrous magnesium silicate. The filtrate is concentrated in vacuo togive the desired product which is purified by flash chromatography togive the desired product as a solid.

EXAMPLE 125 N- 4-(5H-Imidazo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-methylbenzamide

To a stirred solution of 1 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 1.5 mmol of triethylamine. After stirringfor 15 minutes, 1 mmol of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo2,1-c! 1,4!benzodiazepine is added and the mixture stirred for 5 hours.The reaction mixture is washed with water, and brine. The reactionmixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to givea solid which is purified by flash chromatography to give the desiredproduct as a solid.

                  TABLE V                                                         ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 125 with the                                        appropriately substituted aroyl chloride                                      Example                                                                       No.            Compound                                                       ______________________________________                                        126            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2-                                                         chlorobenzamide                                                127            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,5-                                                       dichlorobenzamide                                              128            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,4-                                                       dichlorobenzamide                                              129            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2-                                                         fluorobenzamide                                                130            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2-chloro-                                                  4-methylbenzamide                                              131            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2-methyl-                                                  4-chlorobenzamide                                              132            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,4-                                                       dimethylbenzamide                                              133            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,3-                                                       dimethylbenzamide                                              134            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2-                                                         methoxybenzamide                                               135            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2-                                                         trifluoromethoxybenzamide                                      136            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,-                                                        4-dimethoxybenzamide                                           137            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,-                                                        6-dimethoxybenzamide                                           138            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!                                                            benzamide                                                      139            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,-                                                        6-dichlorobenzamide                                            140            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,-                                                        6-dimethylbenzamide                                            141            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,-                                                        methylthiobenzamide                                            142            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,-                                                        methyl-3-thiophenecarboxamide                                  143            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-3,-                                                        methyl-2-thiophenecarboxamide                                  144            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-2,-                                                        methyl-3-furanecarboxamide                                     145            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!-3,-                                                        methyl-2-furanecarboxamide                                     146            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!                                                            phenylacetamide                                                147            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!                                                            2-chlorophenylacetamide                                        148            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!                                                            2-methylphenylacetamide                                        149            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!                                                            2-methyl-3-thiopheneacetamide                                  150            N- 4-(5H-imidazo 2,1-c! 1,4!-                                                 benzodiazepin-10(11H)-                                                        ylcarbonyl)phenyl!                                                            2-methyl-3-furanacetamide                                      ______________________________________                                    

EXAMPLE 151 N- 4-(7-Chloro-5H-imidazo 2,1-c!1.4!benzodiazepin-10(11H)-ylcarbonyl!phenyl!-2-methylbenzamide

As described for Example 125 a mixture of 1 mmol of7-chloro-10,11-dihydro-5H-imidazo 2,1-c! 1,4!benzodiazepine, 1.1 mmol of4- (2-methylbenzoyl)amino!benzoyl chloride and 1.5 mmol of triethylaminein 10 ml of dichloromethane is stirred at room temperature for 3 hoursand worked up to give the desired product as a solid.

EXAMPLE 152 N- 4-(7-Methoxy-5H-imidazo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl!phenyl!-2-methylbenzamide

As described for Example 125 a mixture of 1.0 mmol of7-methoxy-10,11-dihydro-5H-imidazo 2,1-c! 1,4!benzodiazepine, 1.1 mmolof 4- (2-methylbenzoyl)amino!benzoyl chloride and 1.5 mmol oftriethylamine in 10 ml of dichloromethane is stirred for 3 hours at roomtemperature and worked up to give the product as a solid.

EXAMPLE 153 N- 4-(7,8-Methylenedioxy-5H-imidazo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl!phenyl!-2-methylbenzamide

As described for Example 125 a mixture of 1.0 mmol of7,8-methylenedioxy-10,11-dihydro-5H-imidazo- 2,1-c! 1,4!benzodiazepine,1.1 mmol of 4- (2-methylbenzoyl)amino!benzoyl chloride and 1.5 mmol oftriethylamine in 10 ml of dichloromethane is stirred at room temperaturefor 3 hours and worked up to give the desired product as a solid.

EXAMPLE 154 4,5-Dihydro-5-(4-nitrobenzoyl)pyrrolo 1,2-a!quinoxaline

To a solution of 5 mmol of 4,5-dihydropyrrolo 1,2-a!quinoxaline in 50 mlof methylene chloride under argon is added 10 mmol of triethylaminefollowed by ice bath cooling. A solution of 5 mmol of 4-nitrobenzoylchloride in 10 ml of methylene chloride is added dropwise. Followingcomplete addition, the ice bath is removed and the reaction mixturestirred at room temperature for 2 hours. The volatiles are removed invacuo to give a residue which is dissolved in ethyl acetate. Thesolution is washed with water, 1N HCl, NaHCO₃, and brine. The reactionmixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to givea solid which is purified by flash chromatography to give the desiredproduct (from ethyl acetate) as a solid, m.p. 174°-178° C.

EXAMPLE 155 4,5-Dihydro-5(4-aminobenzoyl)pyrrolo 1,2-a!quinoxaline

A mixture of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo1,2-a!quinoxaline in 10 ml of ethyl alcohol and 10 ml of ethyl acetatecontaining 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reactionmixture is filtered through a pad of diatomaceous earth. The filtrate isconcentrated in vacuo to a solid which is purified by flashchromatography to give the desired product, m.p. 225°-228° C.

EXAMPLE 156 4,5-Dihydro-5(4-aminobenzoyl)pyrrolo 1,2-a!quinoxaline

To a solution of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo1,2-a!quinoxaline in 20 ml of ethyl alcohol is added 0.2 g of 10% Pd/Cand 2.5 mmol of hydrazine followed by stirring and heating under refluxfor 2 hours. The hot reaction mixture is filtered through diatomaceousearth and the filter cake washed with hot chloroform and the filtrateconcentrated in vacuo. The residue is triturated with ethyl acetate andthe mixture filtered to give the desired product as crystals, m.p.225°-228° C.

EXAMPLE 157 N- 4-(pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2-methylbenzamide

To a stirred solution of 1.5 mmol of 2-methylbenzoyl chloride in 10 mlof methylene chloride is added 3 mmol of triethylamine. After stirringfor 15 minutes, 1.5 mmol of 4,5-dihydro-5-(4-aminobenzoyl)pyrrolo1,2-a!quinoxaline is added and the mixture stirred for 5 hours. Thereaction mixture is washed with water, 1N HCl, NaHCO₃, and brine. Thereaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuoto give a solid which is purified by flash chromatography to give thedesired product as a solid, m.p. 206°-207° C.

                  TABLE VI                                                        ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 157 with the                                        appropriateiy substituted aroyl chloride                                      Example                                                                       No.          Compound                                                         ______________________________________                                        158          N- 4-(pyrrolo 1,2-a!quinoxalin-                                               5(4H)ylcarbonyl)phenyl!-2-                                                    chlorobenzamide                                                  159          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2,4-dichloro-                                              benzamide                                                        160          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2,4-dichloro-                                              benzamide, m.p. 200°-202° C.                       161          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2-chloro-4-methyl-                                         benzamide                                                        162          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2-methyl-4-chloro-                                         benzamide                                                        163          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2,4-dimethyl-                                              benzamide                                                        164          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2,3-dimethyl-                                              benzamide, m.p. 216°-220° C.                       165          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2-methoxy-                                                 benzamide                                                        166          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2-trifluoro-                                               methoxybenzamide                                                 167          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2,4-dimethoxy-                                             benzamide                                                        168          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2,6-dimethoxy-                                             benzamide                                                        169          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!benzamide                                      170          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2,6-dichloro-                                              benzamide                                                        171          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2,6-dimethyl-                                              benzamide                                                        172          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2-(methylthio)-                                            benzamide                                                        173          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2-methyl-3-                                                thiophenecarboxamide                                             174          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-3-methyl-2-                                                thiophenecarboxamide                                             175          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2-methyl-3-                                                furanecarboxamide                                                176          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-3-methyl-2-                                                furanecarboxamide                                                177          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-benzeneacetamide                              178          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2-chlorobenzene                                            acetamide                                                        179          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2-methylbenzene                                            acetamide, yellow foam                                           180          N- 4-pyrrolo 1,2-a!quinoxalin-5(4H)-                                          ylcarbonyl)phenyl!-2-methyl-3-                                                thiopheneacetamide                                               ______________________________________                                    

EXAMPLE 181 9,10-Dihydro-4H-furo 2,3-e!pyrrolo 1,2-a! 1,4!diazepine

To a suspension of 4 mmol of lithium aluminum hydride in 25 ml ofanhydrous tetrahydrofuran is added 1 mmol of 9,10-dihydro-4H-furo2,3-e!pyrrolo 1,2-a! 1,4!diazepin-9-one. The mixture is refluxed for 12hours and allowed to stand overnight. To the mixture is added dropwise0.12 ml of water and then 6 ml of 1N sodium hydroxide. The mixture isextracted with ethyl acetate and the extract dried(Na₂ SO₄). Thevolatiles are removed in vacuo to give the desired product as a solid.

EXAMPLE 182 9,10-Dihydro-4H-furo 2,3-e!pyrrolo 1,2-a! 1,4!diazepine

A solution of 1 mmol of 4H-furo 2,3-e!pyrrolo 1,2-a! 1,4!diazepine and0.2 g of 10% Pd/C in 10 ml of 10 ml of ethanol is hydrogenated for 18hours. The reaction mixture is filtered through diatomaceous earth andthe filtrate is evaporated in vacuo to give the desired product as asolid.

EXAMPLE 183 N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!1,4!diazepin-10-(9H)-ylcarbonyl)phenyl!-2-methylbenzamide

To a mixture of 1.1 mmol of 4- (2-methylbenzoyl)amino!benzoyl chloridein 10 ml of methylene chloride, cooled to 0° C. is added 1.5 mmol oftriethylamine. To the mixture is added 1 mmol of 9,10-dihydro-4H-furo2,3-e!pyrrolo 1,2-a! 1,4!diazepine and the mixture stirred at roomtemperature for 2 hours. The reaction mixture is concentrated in vacuoand the residue is dissolved in 100 ml of ethyl acetate and washed withwater, 2N citric acid, aqueous NaHCO₃ and brine. The solution is driedwith Na₂ SO₄ and the volatiles concentrated in vacuo to give a solidwhich is purified by flash chromatography to give the desired product.

EXAMPLE 184 9,10-Dihydro-10-(4-nitrobenzoyl)-4H-furo 2,3-e!pyrrolo1,2-a! 1,4!diazepine

To a solution of 1.0 mmol of 9,10-dihydro-4H-furo 2,3-e!pyrrolo 1,2-a!1,4!diazepine in 10 ml of methylene chloride under argon is added 1.5mmol of triethylamine followed by ice bath cooling. A solution of 1.1mmol of 4-nitrobenzoyl chloride in 5 ml of methylene chloride is addeddropwise. Following complete addition, the ice bath is removed and thereaction mixture is stirred at room temperature for 2 hours. Thevolatiles are removed in vacuo to give a residue which is dissolved inethyl acetate. The solution is washed with water, 1N HCl, NaHCO₃, andbrine. The reaction mixture is dried with Na₂ SO₄, filtered andevaporated in vacuo to give a solid which is purified by flashchromatography on silica gel to give desired product as a solid.

EXAMPLE 185 9,10-Dihydro-10-(4-aminobenzoyl)-4H-furo 2,3-e!pyrrolo1,2-a! 1,4!diazepine

A mixture of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo2,3-e!pyrrolo 1,2-a! 1,4!diazepine in 10 ml of ethyl alcohol and 10 mlof ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5hours. The reaction mixture is filtered through a pad of diatomaceousearth. The filtrate is concentrated in vacuo to a solid which ispurified by flash chromatography on silica gel to give the desiredproduct.

EXAMPLE 186 9,10-Dihydro-10-(4-aminobenzoyl)-4H-furo 2,3-e!pyrrolo1,2-a! 1,4!diazepine

To a solution of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo2,3-e!pyrrolo 1,2-a! 1,4!diazepine in 20 ml of ethyl alcohol is added0.2 g of 10% Pd/C and 2.5 mmol of hydrazine followed by stirring andheating under reflux for 3 hours. The room temperature reaction mixtureis filtered through diatomaceous earth and the filtrate concentrated invacuo. The residue is dissolved in methylene chloride and passed througha thin pad of hydrous magnesium silicate. The filtrate is concentratedin vacuo to give the desired product which is purified by flashchromatography on silica gel to give the desired product as a solid.

EXAMPLE 187 N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!1,4!diazepin-10(9H)-ylcarbonyl)phenyl!-2-methyl benzamide

To a stirred solution of 1.1 mmol of 2-methylbenzoyl chloride in 10 mlof methylene chloride is added 1.5 mmol of triethylamine. To the mixtureis added 1.1 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-furo2,3-e!pyrrolo 1,2-a! 1,4!diazepine and the mixture is stirred for 5hours. The reaction mixture is washed with water, 1N citric acid,NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filteredand evaporated in vacuo to give a solid which is purified by flashchromatography on silica gel with ethyl acetate-hexane as solvent togive the desired product as a solid.

                  TABLE VII                                                       ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 187 with the                                        appropriateiy substituted aroyl chloride                                      Example                                                                       No.          Compound                                                         ______________________________________                                        188          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-chlorobenzamide                                        189          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2,5-dichlorobenzamide                                    190          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2,4-dichlorobenzamide                                    191          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-chloro-4-methylbenzamide                               192          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-methyl-4-chlorobenzamide                               193          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2,4-dimethylbenzamide                                    194          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2,3-dimethylbenzamide                                    195          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-methoxybenzamide                                       196          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-trifluoromethoxybenzamide                              197          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2,4-dimethoxybenzamide                                   198          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-methoxy-4-chlorobenzamide                              199          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2,6-dichlorobenzamide                                    200          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-methylthiobenzamide                                    201          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-methyl-3-thiophene-                                                 carboxamide                                                      202          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-3-methyl-2-thiophene-                                                 carboxamide                                                      203          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-methyl-3-furane-                                                    carboxamide                                                      204          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-3-methyl-2-furane-                                                    carboxamide                                                      205          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-chlorobenzacetamide                                    206          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-methylbenzeneacetamide                                 207          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-2-methyl-3-thiophene-                                                 acetamide                                                        208          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-cyclohexanecarboxamide                                   209          N- 4-(4H-Furo 2,3-e!pyrrolo 1,2-a!-                                            1,4!-diazepin-10(9H)-ylcarbonyl)-                                            phenyl!-cyclohexylacetamide                                      ______________________________________                                    

EXAMPLE 210 N- 4-(4H-Pyrazolo 5,1,c!1,4!benzodiazepin-5(10H)-ylcarbonyl)phenyl!-2-methylbenzamide

To a mixture of 1.37 g of 4- (2-methylbenzoyl)amino!benzoyl chloride in15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml oftriethylamine. To the mixture is added 5 mmol of5,10-dihydro-4H-pyrazolo 5,1-c! 1,4!benzodiazepine. The reaction mixtureis allowed to stir at room temperature for 48 hours and the volatilesare removed in vacuo to give a residue. The residue is dissolved in 100ml of ethyl acetate and washed with water, 2N citric acid, aqueousNaHCO₃ and brine. The solution is dried with Na₂ SO₄ and the solventremoved in vacuo. The residue is purified by flash chromatography onsilica gel with ethyl acetate-hexane to give the desired product, m.p.142°-146° C.

EXAMPLE 211 5,10-Dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo- 5,1-c!1,4!benzodiazepine

To a solution of 10 mmol of 5,10-dihydro-4H-pyrazolo 5,1-c!1,4!benzodiazepine in 50 ml of methylene chloride under argon is added15 mmol of triethylamine followed by ice bath cooling. A solution of 11mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is addeddropwise. Following complete addition, the ice bath is removed and thereaction mixture stirred at room temperature for 2 hours. The volatilesare removed in vacuo to give a residue which is dissolved in ethylacetate. The solution is washed with water, NaHCO₃, and brine. Thereaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuoto give a solid which is purified by flash chromatography on silica gelto give desired product as a solid, m.p. 227°-229° C.

EXAMPLE 212 5,10-Dihydro-5-(4-aminobenzoyl)-4H-pyrazolo- 5,1-c!1,4!benzodiazepine

A mixture of 5 mmol of 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-5,1-c! 1,4!benzodiazepine in 25 ml of ethyl alcohol and 10 ml of ethylacetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. Thereaction mixture is filtered through a pad of diatomaceous earth. Thefiltrate is concentrated in vacuo to a solid which is purified by flashchromatography on silica gel to give the desired product as a tan solid.

EXAMPLE 213 5,10-Dihydro-5-(4-aminobenzoyl)-4H-pyrazolo- 5,1-c!1,4!benzodiazepine

To a solution of 5 mmol of 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-5,1-c! 1,4!benzodiazepine in 25 ml of ethyl alcohol is added 0.3 g of10% Pd/C and 15 mmol of hydrazine. The mixture is heated under refluxfor 3 hours, and the mixture is filtered through diatomaceous earth. Thefiltrate is concentrated in vacuo to a residue which is dissolved inmethylene chloride and passed through a thin pad of hydrous magnesiumsilicate. The filtrate is concentrated in vacuo to give the desiredproduct which is purified by flash chromatography on silica gel to givethe desired product as a solid, exact mass by mass spectrometry: 305.1402 (M+H).

EXAMPLE 214 N- 4-(4H-Pyrazolo 5,1-c!1,4!benzodiazepin-5(10H)-ylcarbonyl)phenyl!-2-methylbenzamide

To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 5 mmol of triethylamine and 3 mmol of5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo- 5,1-c! 1,4!benzodiazepine.The mixture is stirred at room temperature for 5 hours and is thenwashed with water, NaHCO₃, and brine. The organic layer is dried withNa₂ SO₄, filtered and evaporated in vacuo to give a solid which ispurified by flash chromatography on silica gel to give the desiredproduct as a solid, m.p. 142°-146° C.

                  TABLE VIII                                                      ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 214 with the                                        appropriately substituted aroyl chloride.                                     Example                                                                       No.          Compound                                                         ______________________________________                                        215          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-methoxybenzeneacetamide, m.p.                                               185-188° C.                                               216          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2,5-dichlorobenzamide                                            217          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2,4-dichlorobenzamide, colorless                                              foam; exact mass by mass spectro-                                             metry: 479.0896 (M + H)                                          218          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-chloro-4-methylbenzamide                                       219          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-methyl-4-chlorobenzamide                                       220          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2,4-dimethylbenzamide                                            221          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2,3-dimethylbenzamide                                            222          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-methoxybenzamide                                               223          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-trifluoromethoxybenzamide                                      224          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2,4-dimethoxybenzamide                                           225          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2,6-dimethoxybenzamide                                           226          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           benzamide                                                        227          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2,6-dichlorobenzamide                                            228          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2,6-dimethylbenzamide                                            229          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-methylthiobenzamide                                            230          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-methyl-3-thiophenencarboxamide                                 231          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           3-methyl-2-thiophenecarboxamide                                  232          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-methyl-3-furanecarboxamide                                     233          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           3-methyl-2-furanecarboxamide                                     234          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           3-cyclohexenecarboxamide                                         235          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-chlorobenzeneacetamide                                         236          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-methylbenzeneacetamide                                         237          N- 4-(4H-Pyrazolo 5,1-c! 1,4!benzo-                                           diazepin-5(10H)-ylcarbonyl)phenyl!-                                           2-methyl-3H-thiopheneacetamide                                   ______________________________________                                    

EXAMPLE 238 9,10-Dihydro-4H-pyrrolo 1,2-a!thieno 2,3-e! 1,4!diazepine

To a mixture of 7.0 g of 9-oxo-9,10-dihydro-4H-pyrrolo 1,2-a!thieno2,3-e! 1,4!diazepin in 25 ml of anhydrous tetrahydrofuran is added 9 mlof 10 molar boron-dimethylsulfide in tetrahydrofuran. The mixture isrefluxed for 6 hours. The solution is cooled to room temperature and 25ml of methanol added dropwise. The volatiles are removed under vacuum.To the residue is added 100 ml of 2N NaOH. The mixture is refluxed 5hours and filtered. The solid is extracted with dichloromethane and theextract is washed with 2N citric acid, water and dried (Na₂ SO₄). Thesolvent is removed in vacuo to give the desired product as a solid.

EXAMPLE 239 N- 4-(4H-Pyrazolo 1,2-a!thieno 2,3-a!1,4!diazepin-10(9H)-ylcarbonyl)phenyl!-2-methylbenzamide

To a mixture of 1.37 g (5mmol) of 4- (2-methylbenzoyl)amino!benzoylchloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 mlof triethylamine. To the mixture is added 5 mmol of9,10-dihydro-4H-pyrazolo 1,2-a!thieno 2,3-e! 1,4!diazepine. The coolingbath is removed and the reaction mixture is allowed to stir at roomtemperature for 48 hours. The volatiles are removed in vacuo to give aresidue. The residue is dissolved in 100 ml of ethyl acetate and washedwith water, 2N citric acid, aqueous NaHCO₃ and brine. The solution isdried with Na₂ SO₄ and the solvent removed in vacuo to give a solid. Thesolid is purified by flash chromatography on silica gel to give thedesired product.

EXAMPLE 240 9,10-Dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo 1,2-a!thieno2,3-e! 1,4!diazepine

To a solution of 10 mmol of 9,10-dihydro-4H-pyrrolo 1,2-a!thieno 2,3-e!1,4!diazepine in 50 ml of methylene chloride under argon is added 15mmol of triethylamine followed by ice bath cooling. A solution of 11mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is addeddropwise. Following complete addition, the ice bath is removed and thereaction mixture stirred at room temperature for 2 hours. The volatilesare removed in vacuo to give a residue which is dissolved in ethylacetate. The solution is washed with water, 1N HCl, NaHCO₃, and brine.The organic layer is dried with Na₂ SO₄, filtered and evaporated invacuo to give a solid which is purified by flash chromatography onsilica gel to give desired product as a solid.

EXAMPLE 241 9,10-Dihydro-10-(4-aminobenzoyl)-4H-pyrrolo 1,2-a!thieno2,3-e! 1,4!diazepine

A mixture of 2 g of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo-1,2-a!thieno 2,3-e! 1,4!diazepine in 20 ml of ethyl alcohol and 20 ml ofethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours.The reaction mixture is filtered through a pad of diatomaceous earth.The filtrate is concentrated in vacuo to a solid which is purified byflash chromatography to give the desired product.

EXAMPLE 242 9,10-Dihydro-10-(4-aminobenzoyl)-4H-pyrrolo 1,2-a!thieno2,3-e! 1,4!diazepine

To a solution of 5 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo-1,2-a!thieno 2,3-e! 1,4!diazepine in 25 ml of ethyl alcohol is added0.13 g of 10% Pd/C and 15 mmol of hydrazine followed by stirring andheating under reflux for 3 hours. The cooled reaction mixture isfiltered through diatomaceous earth. The filtrate is concentrated invacuo to a residue which is dissolved in methylene chloride and passedthrough a pad of hydrous magnesium silicate. The filtrate isconcentrated in vacuo to give the desired product which is purified byflash chromatography on silica gel to give the desired product as asolid.

EXAMPLE 243 N- 4-(4H-Pyrrolo 1,2-a!thieno 2,3-e!1,4!diazepin-10(9H)-ylcarbonyl)phenyl!-2-methylbenzamide

To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 7 mmol of triethylamine and 5 mmol of9,10-dihydro-10-(4-aminobenzoyl)-4H-pyrrolo- 1,2-a!thieno 2,3-e!1,4!diazepine and the mixture stirred for 5 hours. The reaction mixtureis washed with water, 2N citric acid, NaHCO₃, and brine. The organiclayer is dried with Na₂ SO₄, filtered and evaporated in vacuo to give asolid which is purified by flash chromatography on silica gel to givethe desired product as a solid.

                  TABLE IX                                                        ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 243 with the                                        appropriately substituted aroyl chloride.                                     Example                                                                       No.            Compound                                                       ______________________________________                                        244            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-chloro-                                                    benzamide                                                      245            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2,5-dichloro-                                                benzamide                                                      246            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2,4-dichloro-                                                benzamide                                                      247            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-chloro-                                                    4-methylbenzamide                                              248            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-methyl-                                                    4-chlorobenzamide                                              249            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2,4-                                                         dimethylbenzamide                                              250            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2,3-                                                         dimethylbenzamide                                              251            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-methoxy-                                                   benzamide                                                      252            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-                                                           trifluoromethoxybenzamide                                      253            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2,4-                                                         dimethoxybenzamide                                             254            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2,6-                                                         dimethoxybenzamide                                             255            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2,6-                                                         dichlorobenzamide                                              256            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2,6-                                                         dimethylbenzamide                                              257            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-                                                           methoxy-4-chlorobenzamide                                      258            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-                                                           methoxybenzeneacetamide                                        259            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-(methylthio)-                                              benzamide                                                      260            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-                                                           methyl-3-thiophenecarboxamide                                  261            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-3-methyl-2-                                                  thiophenecarboxamide                                           262            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-3-methyl-2-                                                  furancarboxamide                                               263            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-3-                                                           chlorophenylacetamide                                          264            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-                                                           methylbenzeneacetamide                                         265            N- 4-(4H-pyrrolo 1,2-a!thieno-                                                 2,3-e! 1,4!diazepin-10(9H)-yl                                                carbonyl)phenyl!-2-                                                           methyl-3-thiopheneacetamide                                    ______________________________________                                    

EXAMPLE 266 4,10-Dihydro-5H-pyrrolo 1,2-a!thieno 3,2-e! 1,4!diazepine

To a suspension of 7.0 g of 5-oxo-4,5-dihydropyrrolo 1,2-a!thieno 3,2-e!1,4!diazepine in 25 ml of anhydrous tetrahydrofuran is added 9 ml of 10Mborane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6hours. The solution is cooled to room temperature and 25 ml of methanoladded dropwise. The volatiles are removed under vacuum. To the residueis added 100 ml of 2N NaOH. The mixture is refluxed 5 hours andfiltered. The solid is extracted with dichloromethane and the extract iswashed with 2N citric acid, water and dried (Na₂ SO₄). The solvent isremoved to give a solid.

EXAMPLE 267 N- 4-(5H-Pyrazolo 1,2-a!thieno 3,2-e!1,4!diazepin-4(10H)-ylcarbonyl)phenyl!-2-methylbenzamide

To a mixture of 5.5 mmol of 4- (2-methylbenzoyl)amino!benzoyl chloridein 20 ml of methylene chloride, cooled to 0° C. is added 7.5 mmol oftriethylamine and 5 mmol of 4,10-dihydro-5H-pyrazolo 1,2-a!thieno 3,2-e!1,4!diazepine. The cooling bath is removed and the reaction mixture isallowed to stir at room temperature for 48 hours. The volatiles areremoved in vacuo to give a residue. The residue is dissolved in 100 mlof ethyl acetate and the solution washed with water, 2N citric acid,aqueous NaHCO₃ and brine. The solution is dried with Na₂ SO₄ and thesolvent concentrated in vacuo to give a solid. The solid is purified byflash chromatography on silica gel to give the desired product as asolid and foam, m.p. 162°-188° C., Anal. Calc'd for C₂₅ H₂₁ N₃ O₂ S:C,70.2; H,5.0 N,9.8; S,7.5 Found: C,69.5, H,5.2 N,9.6; S,7.0.

EXAMPLE 268 4,10-Dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo 1,2-a!thieno3,2-e! 1,4!diazepin

To a solution of 3 mmol of 4,10-dihydro-5H-pyrrolo 1,2-a!thieno 3,2-e!1,4!diazepine in 10 ml of methylene chloride under argon is added 5 mmolof triethylamine followed by ice bath cooling. A solution of 3.3 mmol of4-nitrobenzoyl chloride in 3 ml of methylene chloride is added dropwise.Following complete addition, the ice bath is removed and the reactionmixture stirred at room temperature for 2 hours. The volatiles areremoved in vacuo to give a residue which is dissolved in ethyl acetate.The solution is washed with water, 2N citric acid, NaHCO₃, and brine.The reaction mixture is dried with Na₂ SO₄, filtered and evaporated invacuo to give a solid which is purified by flash chromatography onsilica gel to give desired product as a solid.

EXAMPLE 269 4,10-Dihydro-4-(4-aminobenzoyl)-5H-pyrrolo 1,2-a!thieno3,2-e! 1,4!diazepine

A mixture of 5 mmol of 4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-1,2-a!thieno 3,2-e! 1,4!diazepine in 25 ml of ethyl alcohol and 25 ml ofethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours.The reaction mixture is filtered through a pad of diatomaceous earth.The filtrate is concentrated in vacuo to a solid which is purified byflash chromatography on silica gel to give the desired product.

EXAMPLE 270 4,10-Dihydro-4-(4-aminobenzoyl)-5H-pyrrolo 1,2-a!thieno3,2-e! 1,4!diazepine

To a mixture of 5 mmol of 4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-1,2-a!thieno 3,2-e! 1,4!diazepine in 25 ml of ethyl alcohol is added 0.3g of 10% Pd/C and 15 mmol of hydrazine followed by stirring and heatingunder reflux for 3 hours. The cooled reaction mixture is filteredthrough diatomaceous earth. The filtrate is concentrated in vacuo to aresidue which is dissolved in methylene chloride and passed through apad of hydrous magnesium silicate. The filtrate is concentrated in vacuoto give the desired product which is purified by flash chromatography onsilica gel to give the desired product as a solid.

EXAMPLE 271 N- 4-(5H-Pyrrolo 1,2-a!thieno 3,2-e!1,4!diazepin-4(10H)-ylcarbonyl)phenyl!-2-methylbenzamide

To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 5 mmol of triethylamine and 3 mmol of4,10-dihydro-4-(4-aminobenzoyl)-5H-pyrrolo- 1,2-a!thieno 3,2-e!1,4!diazepine. The mixture is stirred for 5 hours. The reaction mixtureis washed with water, 2N citric acid, NaHCO₃, and brine. The reactionmixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to givea solid which is purified by flash chromatography on silica gel to givethe desired product as a solid, m.p. 162°-188° C. (amorphous)

                  TABLE X                                                         ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 271 with the                                        appropriately substituted aroyl chloride.                                     Example                                                                       No.         Compound                                                          ______________________________________                                        272         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-chloro-                                                    benzamide                                                         273         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2,4-dichloro-                                                benzamide                                                         274         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2,4-dichloro-                                                benzamide (solid foam), m.p. 105-                                             190° C.; Anal Calc'd for C.sub.24 H.sub.17 N.sub.3                     Cl.sub.2 O.sub.2 S:                                                           C,59.8; H, 3.6; N, 8.7;                                                       S, 6.6, Cl, 14.7 Found: C, 59.6;                                              H, 3.8; N, 8.1; S, 5.5; Cl, 14.0                                  275         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-chloro-                                                    4-methylbenzamide                                                 276         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-methyl-                                                    4-chlorobenzamide                                                 277         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2,4-dimethyl-                                                benzamide                                                         278         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2,3-dimethyl-                                                benzamide                                                         279         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-methoxy-                                                   benzamide                                                         280         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-trifluoro-                                                 methoxybenzamide                                                  281         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2,4-                                                         dimethoxybenzamide                                                282         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2,6-                                                         dimethoxybenzamide                                                283         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2,6-                                                         dichlorobenzamide                                                 284         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2,6-                                                         dimethylbenzamide                                                 285         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-methylthio-                                                benzamide                                                         286         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-                                                           methyl-3-thiophenecarboxamide                                     287         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-3-                                                           methyl-2-thiophenecarboxamide                                     288         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-3-                                                           methyl-2-furancarboxamide                                         289         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-3-chloro-                                                    benzeneacetamide                                                  290         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-methoxy-                                                   benzeneacetamide                                                  291         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-methoxy-4-                                                 chlorobenzamide                                                   292         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-methylbenzene-                                             acetamide                                                         293         N- 4-(5H-pyrrolo 1,2-a!thieno-                                                 3,2-e! 1,4!diazepin-4(10H)-yl                                                carbonyl)phenyl!-2-                                                           methyl-3-thiopheneacetamide                                       ______________________________________                                    

EXAMPLE 294 6,7-Dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo 1,2-a!1,5!benzodiazepine

To a solution of 10 mmol of 6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepine in 30 ml of methylene chloride under argon is added15 mmol of triethylamine followed by ice bath cooling. A solution of 11mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is addeddropwise. Following complete addition, the ice bath is removed and thereaction mixture stirred at room temperature for 2 hours. The volatilesare removed in vacuo to give a residue which is dissolved in ethylacetate. The solution is washed with water, 2N citric acid, NaHCO₃, andbrine. The reaction mixture is dried with Na₂ SO₄, filtered andevaporated in vacuo to give a solid which is purified by flashchromatography on silica gel to give the desired product as a solid.

EXAMPLE 295 6,7-Dihydro-5-(4-aminobenzoyl)-5H-pyrrolo 1,2-a!1,5!benzodiazepine

A mixture of 2.0 g of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo 1,2-a!1,5!benzodiazepine, 20 ml of ethyl alcohol and 20 ml of ethyl acetatecontaining 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reactionmixture is filtered through a pad of diatomaceous earth. The filtrate isconcentrated in vacuo to a solid which is purified by flashchromatography on silica gel to give the desired product.

EXAMPLE 296 6,7-Dihydro-5-(4-aminobenzoyl)-5H-pyrrolo 1,2-a!1,5!benzodiazepine

To a solution of 5 mmol of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo1,2-a! 1,5!benzodiazepine in 25 ml of ethyl alcohol is added 0.3 g of10% Pd/C and 15 mmol of hydrazine followed by stirring and heating underreflux for 3 hours. The reaction mixture is filtered throughdiatomaceous earth. The filtrate is concentrated in vacuo to a residuewhich is dissolved in methylene chloride and passed through a pad ofhydrous magnesium silicate. The filtrate is concentrated in vacuo togive the desired product which is purified by flash chromatography onsilica gel to give the desired product as a solid.

EXAMPLE 297 N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methylbenzamide

To a mixture of 1.37 g (5 mmol) of 4- (2-methylbenzoyl)amino!benzoylchloride in 10 ml of methylene chloride, cooled to 0° C. is added 7 mmolof triethylamine and 5 mmol of 6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepine. The cooling bath is removed and the reaction mixtureis allowed to stir at room temperature for 48 hours. The volatiles areremoved in vacuo to give a residue. The residue is dissolved in 100 mlof ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO₃and brine. The solution is dried with Na₂ SO₄ and the solvent removed invacuo to give a solid. The solid is triturated with ether-hexane to givethe desired product, mass spectrum (CI): 422(M+H).

EXAMPLE 298 N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl)phenyl!-2-methyl-benzamide

To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml ofmethylene chloride is added 7 mmol of triethylamine and 5 mmol of6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo 1,2-a! 1,5!benzodiazepine. Thereaction mixture is washed with water, 2M citric acid, NaHCO₃, andbrine. The organic layer is dried with Na₂ SO₄, filtered and evaporatedin vacuo to give a solid which is purified by flash chromatography onsilica gel to give the desired product as a solid; mass spectrum (CI):422(M+H).

                  TABLE XI                                                        ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 298 with the                                        appropriately substituted aroyl chloride.                                     Example                                                                       No.            Compound                                                       ______________________________________                                        299            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-                                                           chlorobenzamide                                                300            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2,5-di-                                                      chlorobenzamide                                                301            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2,4-di-                                                      chlorobenzamide                                                302            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-                                                           chloro-4-methylbenzamide                                       303            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-                                                           methyl-4-chlorobenzamide                                       304            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2,4-                                                         dimethylbenzamide                                              305            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2,3-                                                         dimethylbenzamide                                              306            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-                                                           methoxybenazmide                                               307            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-                                                           trifluoromethoxybenzamide                                      308            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2,4-                                                         dimethoxybenzamide                                             309            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2,6-                                                         dimethoxybenzamide                                             310            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2,6-                                                         dichlorobenzamide                                              311            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2,6-                                                         dimethylbenzamide                                              312            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-                                                           methylthiobenzamide                                            313            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-                                                           methyl-3-thiophenecarboxamide                                  314            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-3-                                                           methyl-2-thiophenecarboxamide                                  315            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-                                                           methyl-3-furanecarboxamide                                     316            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-3-methyl-2-                                                  furanecarboxamide                                              317            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!benzeneacetamide                               318            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-chlorobenzene-                                             acetamide                                                      319            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-methylbenzene-                                             acetamide                                                      320            N- 4- (6,7-dihydro-5H-pyrrolo                                                  1,2-a! 1,5!benzodiazepin-5-yl)                                               carbonyl!phenyl!-2-methyl-3-                                                  thiopheneacetamide                                             ______________________________________                                    

EXAMPLE 321 5,6-Dihydro-4H- 1,2,4!triazolo 4,3-a! 1,5!benzodiazepine

A mixture of 7.0 g of 5,6-dihydro-4H- 1,2,4!-triazolo- 4,3-a!1,5!benzodiazepin-5-one in 25 ml of tetrahydrofuran is added 9 ml of 10Mborane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6hours, cooled to room temperature and 25 ml of methanol added dropwise.The volatiles are removed under vacuum and to the residue is added 100ml of 2N sodium hydroxide. The mixture is refluxed for 5 hours, chilledand extracted with dichloromethane. The extract is washed with 2N citricacid, water and dried (Na₂ SO₄). The solvent is removed under vacuum togive a solid. The solid is purified by chromatography on silica gel togive the desired product.

EXAMPLE 322 N- 4-(4H- 1,2,4!triazolo 4,3-a!1,5!benzodiazepin-6(5H)-ylcarbonyl)phenyl!-2-methyl benzamide

To a mixture of 5 mmol of 5,6-dihydro-4H- 1,2,4!triazolo 4,3-a!1,5!benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-(2-methylbenzoyl)amino!benzoyl chloride and then 7.5 mmol oftriethylamine. The mixture is stirred at room temperature for 8 hoursand then washed with water, aqueous NaHCO₃ and brine. The solution isdried (Na₂ SO₄) and the solvent removed in vacuo to give a solid. Thesolid is purified by chromatography on silica gel with ethylacetate-hexane as solvent to give the desired product as a glass.

EXAMPLE 323 5,6-Dihydro-6-(4-nitrobenzoyl)-4H- 1,2,4!triazolo 4,3-a!1,5!benzodiazepine

To a mixture of 3 mmol of 5,6-dihydro-4H- 1,2,4!-triazolo 4,3-a!1,5!benzodiazepine in 10 ml of dichloromethane under argon is added 5mmol of triethylamine. To the mixture is added dropwise 3.3 mmol of4-nitrobenzoyl chloride in 3 ml of dichloromethane. The mixture isstirred at room temperature 3 hours and then washed with water, aqueousNaHCO₃ and brine. The organic layer is dried (Na₂ SO₄) and the solventremoved under vacuum. The residue is purified by chromatography onsilica gel to give the desired product as a solid.

EXAMPLE 324 5,6-Dihydro-6-(aminobenzoyl)-4H- 1,2,4!triazolo 4,3-a!1,4!benzodiazepine

To a mixture of 5 mmol of 5,6-dihydro-6-(4-nitrobenzoyl)-4H-1,2,4!triazolo 4,3-a! 1,4!benzodiazepine in 25 ml of ethanol is added0.3 g of 10% Pd/C and 15 mmol of hydrazine. The mixture is refluxed for3 hours, cooled and filtered through diatomaceous earth. The filtrate isconcentrated in vacuo and the residue purified by chromatography onsilica gel to give the desired product as a solid.

                  TABLE XII                                                       ______________________________________                                        The following Examples are prepared using                                     the conditions of Example 322 with the                                        appropriately substituted aroyl chloride.                                     Example                                                                       No.         Compound                                                          ______________________________________                                        325         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-chlorobenzamide                                                 326         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2,5-dichlorobenzamide                                             327         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2,4-dichlorobenzamide                                             328         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2,3-difluorobenzamide                                             329         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-chloro-4-methylbenzamide                                        330         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-methyl-4-chlorobenzamide                                        331         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2,4-dimethylbenzamide                                             332         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2,3-dimethylbenzamide                                             333         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-methoxybenzamide                                                334         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-trifluoromethoxybenzamide                                       335         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2,3-dichlorobenzamide                                             336         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2,4-dimethoxybenzamide                                            337         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2,6-dimethoxybenzamide                                            338         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-methoxy-4-chlorobenzamide                                       339         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-trifluoromethylbenzamide                                        340         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2,6-dichlorobenzamide                                             341         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2,6-dimethylbenzamide                                             342         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-methylthiobenzamide                                             343         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-methyl-3-thiophenecarboxamide                                   344         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        3-methyl-2-thiophenecarboxamide                                   345         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-methyl-3-furanecarboxamide                                      346         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-methyl-3-furancearboxamide                                      347         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        3-methyl-2-furanecarboxamide                                      348         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-methoxybenzeneacetamide                                         349         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-methylbenzeneacetamide                                          350         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-chlorobenzeneacetamide                                          351         N- 4-(4H- 1,2,4!triazolo 4,3-a! 1,5!                                          benzodiazepin-6(5H)-ylcarbonyl)phenyl!                                        2-methyl-3-thiopheneacetamide                                     ______________________________________                                    

EXAMPLE 352 N- 4-(1-Methyl-4H- 1,2,4!triazolo 4,3-a!1,5!benzodiazepin-6(5H)-ylcarbonyl)phenyl!-2-methyl benzamide

To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H- 1,2,4!triazolo 4,3-a!1,5!benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-(2-methylbenzoyl)amino!benzoyl chloride and 7.5 mmol of triethylamine.The mixture is stirred at room temperature for 8 hours and then washedwith water, aqueous NaHCO₃ and brine. The organic layer is dried (Na₂SO₄) and the solvent removed in vacuo to give a solid. The solid ispurified by chromatography on silica gel with ethyl acetate-hexane assolvent to give the desired product.

EXAMPLE 353 N- 4-(1-Methyl-4H- 1,2,4!triazolo 4,3-a!1,5!benzodiazepin-6(5H)-ylcarbonyl)phenyl!-2,4 dichlorobenzamide

To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H- 1,2,4!triazolo 4,3-a!1,5!benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-(2,4-dichlorobenzoyl)amino!benzoyl chloride and 7.5 mmol oftriethylamine. The mixture is stirred at room temperature for 8 hoursand then washed with water, aqueous NaHCO₃ and brine. The organic layeris dried (Na₂ SO₄) and the solvent removed in vacuo to give a solid. Thesolid is purified by chromatography on silica gel to give the desiredproduct as a solid.

EXAMPLE 354 N-4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11)-ylcarbonyl)phenyl!-3-cyclohexenecarboxamide

A mixture of 0.50 g of 10,11-dihydro-10(4-aminobenzoyl-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 0.286 g of 3-cyclohexenecarbonyl chloride and 346 μlof triethylamine in 5 ml of dichloromethane is stirred at roomtemperature 16 hours. The mixture is diluted with 50 ml ofdichloromethane and the solution washed with 20 ml of water, 2N citricacid, 1N NaHCO₃, brine and dried (Na₂ SO₄). The solution is filteredthrough a thin pad of hydrous magnesium silicate and the filtrateevaporated in vacuo. The residue is chromatographed on thick layersilica gel plates to give a solid which is crystallized from ethylacetate to give 0.34 g of crystals, m.p. 216°-218° C.

EXAMPLE 355 N-4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11)ylcarbonyl)phenyl!-5-methyl-2-thiophenecarboxamide

To a solution of 0.318 g of 5-methyl-2-thiophenecarbonyl chloride in 5ml of dichloromethane cooled to 0° C. is added 0.50 g of10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo 2,1-c! 1,4!benzodiazepineand 346 μl of triethylamine. The mixture is stirred at room temperature16 hours and diluted with 50 ml of dichloromethane. The solution iswashed with 20 ml each of water, 2N citric acid. 1M NaHCO₃, brine anddried (Na₂ SO₄). The solution is filtered through a thin pad of hydrousmagnesium silicate and the filtrate evaporated in vacuo to give a solid.The solid is crystallized from ethyl acetate to give 0.53 g of crystals,m.p. 235°-238° C.

EXAMPLE 356 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11)ylcarbonyl)phenyl!-cyclohexylacetamide

To a solution of 0.318 g of cyclohexylacetyl chloride in 5 ml ofdichloromethane cooled to 0° C. is added 0.50 g of10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo 2,1-c! 1,4!benzodiazepineand 346 μl of triethylamine. The mixture is stirred at room temperature16 hours and diluted with 50 ml of dichloromethane. The solution iswashed with 20 ml each of water, 2N citric acid. 1M NaHCO₃, brine anddried (Na₂ SO₄). The solution is filtered through a thin pad of hydrousmagnesium silicate and the filtrate evaporated in vacuo to give a solid.The solid is crystallized from ethyl acetate to give 0.52 g of crystals,m.p. 231°-234° C.

EXAMPLE 357 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11)ylcarbonyl)phenyl!-2-fluorobenzeneacetamide

To a solution of 0.342 g of 2-fluorophenylacetyl chloride in 5 ml ofdichloromethane cooled to 0° C. is added 0.50 g of10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo 2,1-c! 1,4!benzodiazepineand 346 μl of triethylamine. The mixture is stirred at room temperature16 hours and diluted with 50 ml of dichloromethane. The solution iswashed with 20 ml each of water, 2N citric acid. 1M NaHCO₃, brine anddried (Na₂ SO₄). The solution is filtered through a thin pad of hydrousmagnesium silicate and the filtrate evaporated in vacuo to give a solid.The solid is crystallized from ethyl acetate to give 0.43 g of crystals,m.p. 204°-207° C.

EXAMPLE 358 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11)ylcarbonyl)phenyl!-cyclohexanecarboxamide

To a solution of 0.342 g of cyclohexanecarbonyl chloride in 5 ml ofdichloromethane cooled to 0° C. is added 0.50 g of10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo 2,1-c! 1,4!benzodiazepineand 346 μl of triethylamine. The mixture is stirred at room temperature16 hours and diluted with 50 ml of dichloromethane. The solution iswashed with 20 ml each of water, 2N citric acid. 1M NaHCO₃, brine anddried (Na₂ SO₄). The solution is filtered through a thin pad of hydrousmagnesium silicate and the filtrate evaporated in vacuo to give a solid.The solid is crystallized from ethyl acetate to give 0.54 g of crystals,m.p. 202°-204° C.

EXAMPLE 359 4- N-Methyl-N-(2-methylbenzoylamino!benzoyl chloride

A solution of 6.72 g of 4- N-methyl-N-(2-methylbenzoyl)amino!benzoicacid in 20 ml of thionyl chloride is refluxed for one hour. Thevolatiles are removed in vacuo. Toluene is added to the residue and thenthe toluene removed in vacuo (repeated several times) to give the 7.3 gof product as a brown oil.

EXAMPLE 360 4- N-Methyl-N-(2-methylbenzoyl)amino!benzoic acid

A sample of 1.51 g of sodium hydride (60% in oil) is washed with hexaneunder argon to remove the oil. To the washed sodium hydride is added 5ml of N,N-dimethylformamide. To this mixture is added dropwise asolution of 8.69 g of ethyl 4- (2-methylbenzoyl)amino!benzoate in 20 mlof N,N-dimethylformamide. The mixture is stirred at room temperature for0.5 hour and then 5.23 g of methyl iodide is added. The mixture isstirred at room temperature for 16 hours. The mixture is diluted withwater and extracted with dichloromethane. The extract is dried (Na₂SO₄), concentrated to reduce the volume and the solution filteredthrough a thin pad of hydrous magnesium silicate. The filtrate isconcentrated in vacuo to give 11 g of an oil (1:1 mixture of product andN,N-dimethylformamide). The preceding product, ethyl 4-N-methyl-N-(2-methylbenzoyl)amino!benzoate, (11 g) is dissolved in 30 mlof methanol and 25 ml of 2N NaOH added. The mixture is refluxed for 2hours and the solvent removed. The residue is extracted with ether(discard) and the remaining residue dissolved in 50 ml of water. Thebasic solution is acidified with 2N citric acid and the solid filteredoff and washed with water. The product is air dried to give 6.72 g ofcrystals, m.p. 187°-190° C.

As described for Example 360 but substituting the appropriate ethyl 4-(N-aroyl)amino!benzoate, the following compounds are prepared.

EXAMPLE 361 4- N-Methyl-N-(2-chlorobenzoyl)amino!benzoic acid EXAMPLE362 4- N-Methyl-N-(2,5-dichlorobenzoyl)amino!benzoic acid EXAMPLE 363 4-N-Methyl-N-(2,4-dichlorobenzoyl)amino!benzoic acid EXAMPLE 364 4-N-Methyl-N-(2-chloro-4-methylbenzoyl)amino!benzoic acid EXAMPLE 365 4-N-Methyl-N-(2-methyl-4-chlorobenzoyl)amino!benzoic acid EXAMPLE 366 4-N-Methyl-N-(2,4-dimethylbenzoyl)amino!benzoic acid EXAMPLE 367 4-N-Methyl-N-(2,3-dimethylbenzoyl)amino!benzoic acid EXAMPLE 368 4-N-Methyl-N-(2-methoxybenzoyl)amino!benzoic acid EXAMPLE 369 4-N-Methyl-N-(2-trifluoromethoxybenzoyl)amino!benzoic acid EXAMPLE 370 4-N-Methyl-N-(2,4-dimethoxybenzoyl)amino!benzoic acid EXAMPLE 371 4-N-Methyl-N-(2-methoxy-4-chlorobenzoyl)amino!benzoic acid EXAMPLE 372 4-N-Methyl-N-(2-methylthiobenzoyl)amino!benzoic acid EXAMPLE 373 4-N-Methyl-N-(2-methylthiophen-3-ylcarbonyl)amino!benzoic acid EXAMPLE 3744- N-Methyl-N-(3-methylthiophene-2-ylcarbonyl)amino!benzoic acid EXAMPLE375 4- N-Methyl-N-(2-methylfuran-3-ylcarbonyl)amino!benzoic acid EXAMPLE376 4- N-Methyl-N-(3-methylfuran-2-ylcarbonyl)amino!benzoic acid EXAMPLE377 4- N-Methyl-N-(phenylacetyl)amino!benzoic acid EXAMPLE 378 4-N-Methyl-N-(2-chlorophenylacetyl)amino!benzoic acid EXAMPLE 379 4-N-Methyl-N-(2-methoxyphenylacetyl)amino!benzoic acid EXAMPLE 380 4-N-Methyl-N-(2-methylphenylacetyl)amino!benzoic acid EXAMPLE 381 4-N-Methyl-N-(cyclohexylcarbonyl)amino!benzoic acid EXAMPLE 382 4-N-Methyl-N-(3-cyclohexenecarbonyl)amino!benzoic acid EXAMPLE 383 4-N-Methyl-N-(cyclohexylacetyl)amino!benzoic acid EXAMPLE 384 N-4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-methylbenzamide

A mixture of 0.27 g of 10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 0,518 g of 4-N-methyl-N-(2-methylbenzoyl)amino!benzoyl chloride, 0.182 g oftriethylamine and 7 ml of tetrahydrofuran is stirred at room temperaturefor 3 hours. To the mixture is added 0.29 g of 4-N-methyl-N-(2-methylbenzoyl)amino!benzoyl chloride and 0.10 g oftriethylamine in 2 ml of dichloromethane and the mixture stirred for 2days. The mixture is poured into water and extracted withdichloromethane. The extract is washed with water, 1N HCl, 1N NaHCO₃,brine and dried (Na₂ SO₄). The solution is filtered through a thin padof hydrous magnesium silicate. The filtrate is evaporated in vacuo andthe residue crystallized from dichloromethane-hexane to give 0.38 g ofcrystals, m.p. 168°-170° C.

As described for Example 384, but substituting the appropriate aroylchloride, the following compounds are prepared.

EXAMPLE 385 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-chlorobenzamideEXAMPLE 386 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2,5-dichlorobenzamideEXAMPLE 387 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-chloro-4-methylbenzamideEXAMPLE 388 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-methyl-4-chlorobenzamideEXAMPLE 389 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2,4-dimethylbenzamideEXAMPLE 390 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2,3-dimethylbenzamideEXAMPLE 391 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-methoxybenzamideEXAMPLE 392 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-trifluoromethoxybenzamideEXAMPLE 393 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2,4-dimethoxybenzamideEXAMPLE 394 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-methoxy-4-chlorobenzamideEXAMPLE 395 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-methylthiobenzamideEXAMPLE 396 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-methyl-3-thiophenecarboxamideEXAMPLE 397 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-3-methyl-2-thiophenecarboxamideEXAMPLE 398 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-methyl-3-furanecarboxamideEXAMPLE 399 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methylbenzeneacetamideEXAMPLE 400 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-chlorobenzeneacetamideEXAMPLE 401 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-methoxybenzeneacetamideEXAMPLE 402 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-methylbenzeneacetamideEXAMPLE 403 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-2-methyl-3-thiopheneacetamideEXAMPLE 404 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methylcyclohexanecarboxamideEXAMPLE 405 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methylcyclohexylacetamideEXAMPLE 406 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-N-methyl-3-cyclohexenecarboxamideEXAMPLE 407 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)-2-methylphenyl!-2,4-dichlorobenzamide

A mixture of 0.40 g of10,11-dihydro-10-(3-methyl-4-aminobenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 0.40 g of 2,4-dichlorobenzoyl chloride and 0.75 g ofdiisopropylethylamine in 50 ml of dichloromethane is stirred at roomtemperature for 16 hours. The mixture is washed with water, dried(MgSO₄) and the solution passed through a thin pad of hydrous magnesiumsilicate. The filtrate is concentrated and hexane added to givecrystals. Recrystallization from dichloromethane-hexane gives 0.52 g ofcrystals, m.p. 213°-215° C.

EXAMPLE 408 1-(2-Nitrophenyl)-1H-pyrrole-2-carboxaldehyde

A sample of 4.7 g of sodium hydride (60% in oil) is washed with hexane(under argon). To the sodium hydride is added 200 ml of dryN,N-dimethylformamide and the mixture is chilled to 0° C. To the mixtureis added 10.11 g of pyrrole-2-carboxaldehyde in small portions. Themixture is stirred 10 minutes and 15.0 g of 1-fluoro-2-nitrobenzeneadded dropwise. After the addition, the mixture is stirred at roomtemperature 16 hours and the mixture concentrated (65° C.) under highvacuum. To the residue is added 400 ml of dichloromethane and themixture washed with 150 ml each of H₂ O, brine and dried (Na₂ SO₄). Thesolvent is removed in vacuo to give a yellow solid. Crystallization fromethyl acetate-hexane (9:1) gives 17.0 g of light yellow crystals, m.p.119°-122° C.

EXAMPLE 409 4,10-Dihydro-5H-pyrrolo 1,2-a!thieno 3,2-e! 1,4!diazepine

To an ice cooled mixture of 2.1 g of pyrrole-2-carboxylic acid and 3.2 gof methyl 3-aminothiophene-2-carboxylate in 40 ml of dry dichloromethaneis added 4 g of N,N-dicyclohexylcarbodiimide. The mixture is stirred atroom temperature for 3 hours and filtered. The filter cake is washedwith dichloromethane and then extracted twice with 60 ml of acetone. Theacetone extract is concentrated to dryness to give 0.8 g of solid, m.p.214°-218° C. To a suspension of the preceding compound (1.19 g) in 20 mlof dry tetrahydrofuran is added 0.2 g of sodium hydride (60% in oil).After the hydrogen evolution, the mixture is stirred and refluxed for4.5 hours, cooled and poured into ice-water. The precipitated solid isfiltered and the solid triturated with petroleum ether (bp 30°-60° C.)to give 0.75 g of 4,10-dihydro-4,10-dioxo-5H-pyrrolo 1,2-a!thieno 3,2-e!1,4!diazepine as a solid, m.p. 280°-290° C. The preceding compound(0.362 g) is added to an ice-water cooled solution of 1M diborane intetrahydrofuran. The mixture is stirred at room temperature for 65hours. The solution is concentrated to dryness and ice-water added tothe residue. The mixture is acidified with dilute HCl, stirred and thenbasified with solid NaHCO₃. The mixture is filtered to give 0.223 g of asolid (foam) m.p. 80°-85° C.

EXAMPLE 410 10,11-Dihydro-5H-1,2,4-triazolo 3,4-c! 1,4!benzodiazedine

A mixture of 2.2 g of 2-cyanoaniline, 2.0 g of methyl bromoacetate and1.3 g of potassium carbonate in 12 ml of dry N,N-dimethylformamide isheated at 150°-155° C. for 40 minutes. The cooled mixture is poured intoice-water and the mixture filtered to give 2 g of methylN-(2-cyanophenyl)amino!acetate as a yellow solid, m.p. 70°-78° C. Thepreceding compound (2.0 g) is added to a solution of 0.5 g of sodiummethoxide in 50 ml of methanol. The mixture is shaken under anatmosphere of hydrogen with the catalyst Raney-Ni for 19 hours. Themixture is filtered through diatomaceous earth and the filtrateevaporated. Water is added to the residue and the mixture filtered togive 2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-3-one as a yellow solid,m.p. 167°-170° C.

A mixture of the preceding compound (1.6 g) and 0.84 g of phosphoruspentasulfide in 10 ml of dry (dried over KOH) pyridine is stirred andheated at 80°-85° C. for 15 minutes. The mixture is poured into waterand stirred for 30 minutes. Filtration gives 1.0 g of1,2,4,5-tetrahydro-3H-1,4-benzodiazepin-3-thione as yellow solid, m.p.150°-153° C.

The preceding compound (0.5 g) and 0.5 g of N-formylhydrazine in 6 ml ofdry n-butanol is refluxed for 16 hours and the solvent removed. Thegummy residue is triturated with cold water and the mixture filtered.The solid is triturated with acetone to give 0.19 g of yellow solid,m.p. 232°-237° C.

EXAMPLE 411 4,5-Dihydro-6H- 1,2,4!triazolo 4,3-a! 1,5!benzodiazepine

A mixture of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione (0.8 g)and 0.80 g of N-formylhydrazine in 8 ml of n-butanol is stirred andrefluxed for 18 hours and the solvent removed under vacuum. Ice water isadded to the residual solid and the mixture filtered to give 0.312 g ofa gray solid, m.p. 162°-165° C.

EXAMPLE 412 4,5-Dihydro-6H-imidazo 1,2-a! 1,5!benzodiazepine

A mixture of 30 g of acrylic acid, 33 g of o-phenylenediamine is heatedon a steam bath for 1.5 hours and the cooled black mixture trituratedwith ice-water. The aqueous phase is decanted and ice and aqueousammonium hydroxide added to the residue. The mixture is extracted withdichloromethane and the extract concentrated to dryness. The residue istriturated with carbon tetrachloride and filtered. The oily solid istriturated with a small amount of ethanol to give 9.7 g of a solid.Trituration of the solid with ethyl acetate gives2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one as an impure solid, m.p.75°-107° C.

A mixture of the preceding compound (11.3 g) and 5.9 g of phosphoruspentasulfide in 70 ml of dry pyridine is stirred and heated atapproximately 80° C. for 20 minutes. The mixture is poured into waterand the mixture stirred for 30 minutes. Filtration gives 8.6 g of2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione as a solid, m.p.154°-157° C.

A mixture of the preceding compound (0.70 g), 1.0 g of aminoacetaldehydedimethyl acetal and 15 mg of 4-methylbenzenesulfonic acid monohydrate in6 ml of dry n-butanol is refluxed for 4 hours and the solvent removedunder vacuum. The residue is heated (refluxed) with 10 ml of 3Nhydrochloric acid for 55 minutes. Ice is added to the cooled mixture andthe mixture made basic with solid NaHCO₃. The mixture is extracted withdichloromethane and the extract dried (Na₂ SO₄). The solvent is removedto give an orange syrup which solidified on standing. The oily solid istriturated with acetone to give a light yellow solid (0.185 g) m.p.119°-122° C.

EXAMPLE 413 1-(2-Nitrophenyl)-2-pyrroleacetic acid, ethyl ester

To a stirred mixture of 1.88 g of 1-(2-nitrophenyl)pyrrole, 4.80 g ofethyl iodoacetate and 2.22 g of FeSO₄.7H₂ O in 40 ml of dimethylsulfoxide is added dropwise 10 ml of 30% hydrogen peroxide while keepingthe reaction mixture at room temperature with a cold water bath. Themixture is stirred at room temperature for one day. An additional 2.4 gof ethyl iodoacetate, 1.1 g of FeSO₄.7H₂ O and 5 ml of 30% hydrogenperoxide is added and the mixture stirred at room temperature for 1 day.The mixture is diluted with water and extracted with diethyl ether. Theorganic extract is washed with water, brine and dried (Na₂ SO₄). Thesolvent is removed and the residue (2.12 g) chromatographed on silicagel with ethyl acetate-hexane (1:4) as solvent to give 0.30 g of productas a brown gum.

EXAMPLE 414 6,7-Dihydro-5H-pyrrolo 1,2-a! 1,5!benzodiazepin-6-one

To a solution of 0.8 mmol of 1-(2-nitrophenyl)-2-pyrroleacetic acid,ethyl ester in 3 ml of ethanol is added stannus chloride dihydrate(SnCl₂.2H₂ O) in 2 ml of concentrated hydrochloric acid (with cooling inwater bath). The mixture is stirred at room temperature for 5 hours andchilled in an ice bath. To the mixture is added slowly saturated sodiumcarbonate solution. The solid which precipitates is filtered and thesolid washed with water and then extracted with ethyl acetate. The ethylacetate extract is dried (Na₂ SO₄) and the solvent removed to give 0.16g of solid which is triturated with ether to give 0.11 g of product asan off-white solid.

EXAMPLE 415 6,7-Dihydro-5H-pyrrolo 1,2-a! 1,5!benzodiazepine

To a solution of 0.070 g of 6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-6-one in 2 ml of tetrahydrofuran is added 0.45 ml of a2.0M solution of diborane-dimethylsulfide in tetrahydrofuran. Themixture is refluxed for 3 hours, poured into water and make basic with2N NaOH. The tetrahydrofuran is removed under vacuum and the residualaqueous mixture extracted with diethyl ether. The extract is washed withbrine, dried (Na₂ SO₄) and the solvent removed to give 0.065 g of acolorless oil; one spot by thin layer chromatography (silica gel) withethyl acetate-hexane (1:2) as solvent (Rf 0.81).

EXAMPLE 416 10,11-Dihydro-10-(2-chloro-4-aminobenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine

A mixture of 5.0 g of 10,11-dihydro-10-(2-chloronitrobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine, 15.4 g of stannus chloride and 170 ml ofethanol is heated at 70°-80° C. for 1 hour. The mixture is chilled (icebath) and made basic with 1M NaHCO₃ solution (350 ml) and then stirredat room temperature for 1 hour. The mixture is brought to pH 5 withacetic acid and extracted with 500 ml of ethyl acetate and with 300 mlof ethyl acetate. The combined extract is washed with 250 ml of brineand dried (Na₂ SO₄). The solution is filtered through a thin pad ofhydrous magnesium silicate and the filter pad washed with ethyl acetate.The filtrate is concentrated to dryness and the residue dissolved in 200ml of hot chloroform-methanol (1:1) and the solution filtered through athin pad of hydrous magnesium silicate. The filtrate is concentratedunder vacuum to give 4.36 g (after drying under vacuum at 60° C.overnight) of product as a white solid. A sample is recrystallized fromchloroform-methanol to give white crystals, m.p. 210°-212° C.

EXAMPLE 417 4- (5-Fluoro-2-methylbenzoyl)amino!benzoic acid

A mixture of 0.60 g of ethyl 4- (5-fluoro-2-methylbenzoyl)amino!benzoate0.60 ml of 10N NaOH, 25 ml of water and 50 ml of absolute ethyl alcoholis heated on a steam bath for 1 hour, cooled and acidified with aceticacid. The resulting solid is filtered and dried in vacuo at 60°-80° C.to give 0.47 g of the desired product as a solid, m.p. 272°-275° C.

The following Examples are prepared using the conditions of Example 417.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        418          4- (3-fluoro-2-methylbenzoyl)amino!-                                          benzoic acid, m.p. 309-311° C.                            419          4- (5-fluoro-2-methylbenzoyl)amino!-2-                                        chlorobenzoic acid, m.p. 247-249° C.                      420          4- 3-fluoro-2-methylbenzoyl)amino!-2-                                         chlorobenzoic acid, m.p. 260-263° C.                      421          4- (3-fluoro-3-(trifluoromethyl)!benzo-                                       yl!amino!-2-chlorobenzoic acid                                   422          4-  2-fluoro-3-(trifluoromethyl)!benzo-                                       yl!amino!-2-chlorobenzoic acid                                   423          4- 2,5-difluorobenzoyl)amino!-2-chloro-                                       benzoic acid                                                     424          4- (2,5-dichlorobenzoyl)amino!-2-chloro-                                      benzoic acid                                                     425          4- (2,3-dimethylbenzoyl)amino!-2-chloro-                                      benzoic acid                                                     426          4- (2,3-dichlorobenzoyl)amino!-2-chloro-                                      benzoic acid                                                     427          4- (2,5-dimethylbenzoyl)amino!-2-chloro-                                      benzoic acid                                                     428          4- 2,3-difluorobenzoyl)amino!-2-chloro-                                       benzoic acid                                                     ______________________________________                                    

EXAMPLE 429 4- (2,4-Dichlorobenzoyl)amino!-2-chlorobenzoic acid

To a stirred mixture of 5.19 g of 2-chloro-4-aminobenzoic acid in 150 mlof methylene chloride is added 7.86 g of N,N-diisopropylethylamine and12.67 g of 2,4-dichlorobenzylchloride and stirring continued for 18hours. Water is added to the filtrate and the organic layer dried withNa₂ SO₄ and concentrate in vacuo to give 13.68 g of the desired product,m.p. 171°-175° C.

The following Examples are prepared using the conditions of Example 429.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        430          4- (2-methylbenzoyl)amino!-2-chloro-                                          benzoic acid, m.p. 196-199° C.                            431          4- (2-methylbenzoyl)amino!-3,5-di-                                            methylbenzoic acid, m.p. 286-289° C.                      432          4- (2,4-dichlorobenzoyl)amino!-3,5-                                           dimethylbenzoic acid, m.p. 209-212° C.                    433          4- (2-methylbenzoyl)amino!-3-chloro-                                          benzoic acid, m.p. 199-202° C.                            434          4- (2,5-dichlorobenzoyl)amino!-2-                                             chlorobenzoic acid                                               435          4- (3-fluoro-2-methylbenzoyl)amino!-3-                                        chlorobenzoic acid, m.p. 225-227° C.                      436          4- (5-fluoro-2-methylbenzoyl)amino!-3-                                        chlorobenzoic acid, m.p. 182-185° C.                      437          4- (2,3-dimethylbenzoyl)amino!-3-                                             chlorobenzoic acid                                               438          4- (2,3-dichlorobenzoyl)amino!-3-                                             chlorobenzoic acid                                               439          4- (2,5-dimethylbenzoyl)amino!-3-                                             chlorobenzoic acid                                               440          4-  4-fluoro-2-(trifluoromethyl)benzoyl!                                      amino!-3-chlorobenzoic acid                                      441          4-  3-fluorobenzoyl!amino!-2-chloro-                                          benzoic acid, m.p. 249-252° C.                            442          4-  2-(trifluoromethyl)benzoyl!amino!-                                        3-chlorobenzoic acid                                             ______________________________________                                    

EXAMPLE 443 Ethyl 10,11-dihydro-10-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine-3-carboxylate

To 25 ml of absolute ethanol is added 0.12 g of sodium metal withstirring followed by 0.68 g of10,11-dihydro-10-(2-chloro-4-nitrobenzoyl)-3-(tri-chloroacetyl)!-5H-pyrrolo 2,1-c! 1,4!benzodiazepine.

Stirring is continued for 18 hours. The volatiles are removed in vacuoto a residue which is partitioned between methylene chloride and water.The organic layer is separated, dried with Na₂ SO₄ and filtrate heatedon a steam bath while hexane is added to give 0.45 g of the desiredproduct as a solid, m.p. 165°-166° C.

The following Examples are prepared using the conditions of Example 443.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        444          ethyl 10,11-dihydro-10-(3-methyl-4-                                           nitrobenzoyl)-5H-pyrrolo 2,1-c! 1,4!-                                         benzodiazepine-3-carboxylate, m.p.                                            200-202  C.                                                      445          ethyl 10,11-dihydro-10-(2-methyl-4-                                           nitrobenzoyl)-5H-pyrrolo 2,1-c! 1,4!-                                         benzodiazepine-3-carboxylate                                     446          ethyl 10,11-dihydro-10-(2-chloro-4-                                           nitrobenzoyl)-5H-pyrrolo 2,1-c! 1,4!-                                         benzodiazepine-3-carboxylate                                     447          ethyl 10,11-dihydro-10-(3-chloro-4-                                           nitrobenzoyl)-5H-pyrrolo 2,1-c! 1,4!-                                         benzodiazepine-3-carboxylate                                     ______________________________________                                    

EXAMPLE 448 10,11-Dihydro-10-(3-methyl-4-nitrobenzoyl)-3-tri-chloroacetyl)!-5H-pyrrolo 2,1-c! 1,4!benzodiazepine

To a stirred solution of 3.47 g of10,11-dihydro-10(4-nitro-3-methylbenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine in 50 ml of methylene chloride is added 3.40 g oftrichloroacetic anhydride and stirring continued for 18 hours. Water isadded and the separated organic layer washed with saturated sodiumbicarbonate, dried with Na₂ SO₄ and passed through a short pad ofhydrous magnesium silicate. Hexane is added to the filtrate at the boilto give 4.07 g of the desired product as a solid. MASS SPEC (CI)491(MH⁺).

The following Examples are prepared using the conditions of Example 448.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        449          10,11-dihydro-10-(4-nitrobenzoyl)- 3-                                         (trichloroacetyl)!-5H-pyrazolo 2,1-c!-                                         1,4!benzodiazepine, m.p. 122-123° C.                     450          10,11-dihydro-10-(2-chloro-4-nitro-                                           benzoyl)- 3-(trichloroacetyl)!-5H-                                            pyrrolo 2,1-c! 1,4!benzodiazepine, m.p.                                       149-151° C.                                               ______________________________________                                    

EXAMPLE 451 10,11-Dihydro-10-(4-nitrobenzoyl)-3-(trifluoroacetyl)!-5H-pyrrolo 2,1-c! 1,4!benzodiazepine

A mixture of 0.50 g of 10,11-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine in 10 ml of methylene chloride is cooled in anice bath and 2.0 g of trifluoroacetic anhydride added. The bath isremoved and the reactants stirred for 18 hrs, partitioned with saturatedsodium bicarbonate and the separated organic layer dried with Na₂ SO₄then passed through a short pad of hydrous magnesium silicate. Thefiltrate is heated at the boil while hexane is added to give 0.40 g ofthe desired product, m.p. 169°-170° C.

The following Examples are prepared using the conditions of Example 451.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        452          10,11-dihydro-10-(2-chloro-4-nitro-                                           benzoyl) 3-(trifluoroacetyl)!-5H-                                             pyrrolo 2,1-c! 1,4!benzodiazepine, m.p.                                       151-153° C.                                               453          10,11-dihydro-10-(3-chloro-4-nitro-                                           benzoyl) 3-(trifluoroacetyl)!-5H-                                             pyrrolo 2,1-c! 1,4!benzodiazepine                                454          10,1-dihydro-10-(2-methyl-4-nitro-                                            benzoyl) 3-(trifluoroacetyl)!-5H-                                             pyrrolo 2,1-c! 1,4!benzodiazepine                                ______________________________________                                    

EXAMPLE 455 10,11-Dihydro-10-(3-methoxy-4-nitrobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine

A mixture of 5.0 g of 3-methoxy-4-nitrobenzoic acid and 5.0 g of thionylchloride is heated under argon for 1 hour. The volatiles are removed invacuo to give 2.85 g of a 3-methoxy-4-nitrobenzoyl chloride as a residuewhich is dissolved in 50 ml of methylene chloride. To the precedingsolution is added with stirring 1.75 g of N,N-diisopropylethylaminefollowed by 1.84 g of 10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine. The reaction mixture is stirred under argon for 18hours and diluted with saturated sodium bicarbonate. The organic layeris dried with Na₂ SO₄ and passed through a short pad of hydrousmagnesium silicate. While boiling, hexane is added to the filtrate togive, upon cooling, 3.39 g of the desired product as a solid, m.p.191°-192° C.

The following Examples are prepared using the conditions of Example 455.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        456          10,11-dihydro-10-(2-methoxy-4-nitro-                                          benzoyl)-5H-pyrrolo 2,1-c! 1,4!benzo-                                         diazepine                                                        457          10,11-dihydro-10-(2-methyl-4-nitro-                                           benzoyl)-5H-pyrrolo 2,1-c! 1,4!-                                              benzodiazepine                                                   458          10,11-dihydro-10-(3-methoxy-6-chloro-                                         4-nitrobenzoyl)-5H-pyrrolo 2,1-c! 1,4!-                                       benzodiazepine                                                   459          10,11-dihydro-10-(3-methoxy-6-methyl-4-                                       nitrobenzoyl)-5H-pyrrolo 2,1-c! 1,4!-                                         benzodiazepine                                                   ______________________________________                                    

EXAMPLE 460 10,11-Dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine

A mixture of 3.24 g of10,11-dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 0.35 g of 10% Pd/c and 0.60 g of anhydrous hydrazinein 100 ml of absolute ethyl alcohol and heated on a steam bath for 1hour. The hot reaction mixture is filtered through diatomaceous earthand the filtrate evaporated in vacuo to a residue which is partitionedbetween methylene chloride and water. The organic layer is dried withNa₂ SO₄ and passed through a short pad of hydrous magnesium silicate.Hexane is added to the filtrate while heating on a steam bath to give 2g of crystals, m.p. 184°-185° C.

The following Examples are prepared using the conditions of Example 460.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        461          10,11-dihydro-10-(4-amino-2-chloro-                                           benzoyl)-5H-pyrrolo 2,1-c! 1,4!benzo-                                         diazepine, m.p. 197-199° C.                               462          10,11-dihydro-10-(4-aminobenzoyl) 3-                                          (trifluoroacetyl)!-5H-pyrrolo 2,1-c!-                                          1,4!benzodiazepine, m.p. 200-206° C.                     463          ethyl 10,11-dihydro-10-(4-amino-3-                                            methylbenzoyl)-5H-pyrrolo 2,1-c!-                                              1,4!benzodiazepine-3-carboxylate, m.p.                                       210-211° C.                                               464          ethyl 10,11-dihydro-10-(4-aminobenzoyl)-                                      5H-pyrrolo 2,1-c! 1,4!benzodiazepine-3-                                       carboxylate, m.p. 174-175° C.                             ______________________________________                                    

EXAMPLE 465 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-5-fluoro-2-methylbenzamide

To a stirred solution of 500 mg of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepinein 3 ml of methylene chloride, cooled to 0° C., under argon, is added346 μl of triethylamine followed by the addition of 340 mg of2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride. Thecooling bath is removed and stirring continued for 18 hours. Aftercooling to 0° C., an additional 342 mg of 2-methyl-5-fluorobenzoylchloride in 2 ml of methylene chloride is added. The cooling bath isremoved and stirring continued for 18 hours. The volatiles are removedin vacuo to a residue which is dissolved in 50 ml of methylene chlorideand washed with 20 ml each of water, 2N citric acid, 1M sodiumbicarbonate and brine. The organic layer is dried over Na₂ SO₄ andpassed through a pad of hydrous magnesium silicate. The filtrate isevaporated in vacuo to a residue which is crystallized from ethylacetate-hexane to give 295 mg of the desired product as a white solid,m.p. 170°-180° C.

The following Examples are prepared using the conditions of Example 465with the appropriately substituted aroyl chloride.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        466          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodia-                                         zepin-10(11H)-ylcarbonyl)phenyl!-3-                                           fluoro-2-methylbenzamide, m.p. 194-208° C.                467          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-2,3-di-                                        methylbenzamide, m.p. 168-170° C.                         468          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-2,3-                                           dichlorobenzamide, m.p. 219-222° C.                       469          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-2,6-di-                                        chlorobenzamide, m.p. 174-182° C.                         470          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl-3-chlorophenyl!-                                       2-methylbenzamide, m.p. 190-195° C.                       471          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl-3-chlorophenyl!-                                       2,4-dichlorobenzamide, m.p. 144-160° C.                   472          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl-2,6-dimethyl                                           phenyl!-2-methylbenzamide, amorphous                                          solid                                                            473          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl-2,6-dimethyl                                           phenyl!-2,4-dichlorobenzamide, amorphous                                      solid                                                            474          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-3-(tri-                                        fluoromethyl)benzamide, amorphous                                             solid                                                            475          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chloro-                                             phenyl!-3-methylthiophene-2-carboxamide                          476          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-3-                                             chlorothiophene-2-carboxamide, solid;                                         MASS SPEC (CI):448 (M+H)                                         477          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-methoxy-                                            phenyl!-2-methylbenzamide, m.p. 184-                                          186° C.                                                   478          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-methoxy-                                            phenyl!-2,4-dichlorobenzamide, m.p.                                           192-194° C.                                               479          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-methoxy-                                            phenyl!-3-fluoro-2-methylbenzamide                                            m.p. 203-204° C.                                          480          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-2-chloro-                                      5-nitrobenzamide,                                                             m.p. 110-160° C. (amorphous solid)                        267          N-(5H-pyrrolo 1,2-a!thieno 3,2-e! 1,4!-                                       diazepin-4(10H)-ylcarbonyl)phenyl!-                                           2-methylbenzamide, m.p. 162-188° C.                                    (amorphous solid)                                                274          N- 4-(5H-pyrrolo 1,2-a!thieno 3,2-e!-                                          1,4!-diazepin-4(10H)-ylcarbonyl)-                                            phenyl!-2,4-dichlorobenzamide, m.p.                                           105-190° C.                                               ______________________________________                                    

EXAMPLE 481 N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl!-3-fluoro-2-methylbenzamide

To a solution of 1.50 g of 10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine in 25 ml of methylene chloride is added 1.23 g ofN,N-diisopropylethylamine. While cooling in an ice bath, a solution of3.08 g of 4- (2-methyl-5-fluorobenzoyl)amino!-2-chlorobenzoyl chloridein 50 ml of methylene chloride is added. The reaction mixture becomeshomogeneous and is stirred at room temperature for 18 hours. Water isadded and the separated organic layer washed with saturated sodiumbicarbonate, dried with Na₂ SO₄ and passed through a short pad ofhydrous magnesium silicate two times. The methylene chloride is removedin vacuo to give 3.81 g of a glass. A sample is crystallized from ethylacetate to give crystalline solid, m.p. 200°-205° C.

EXAMPLE 482 N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl!-5-fluoro-2-methylbenzamide

To a solution of 1.84 g of 10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine in 25 ml of methylene chloride is added 1.30 g ofN,N-diisopropylethylamine. While cooling in an ice bath, a solution of3.45 g of 4- (2-methyl-5-fluorobenzoyl)amino!-2-chlorobenzoyl chloridein 50 ml of methylene chloride is added. The reaction mixture becomeshomogeneous after 5 minutes and is stirred at room temperature for 18hours. Water is added and the separated organic layer washed withsaturated sodium bicarbonate, dried with Na₂ SO₄ and passed through ashort pad of hydrous magnesium silicate. The methylene chloride isremoved in vacuo to give 4.60 g of the desired product as a glass. Asample is crystallized from ethyl acetate to give crystalline solid,m.p. 191°-195° C.

EXAMPLE 483 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)benzoic acid

A solution of 0.92 g of 10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 1.19 g of monomethyl terephthaloyl chloride in 20 mlof pyridine is refluxed for 2 hours. The mixture is chilled and 1N HCladded until the pH is 5. The mixture is filtered and washed with waterto give 1.53 g of solid. Recrystallization from dichloromethane-hexanegives crystals, m.p. 186°-188° C. of methyl 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl-carbonyl)benzoate.

A mixture of 1.83 g of the preceding compound, 8 ml of 2N NaOH and 14 mlof methanol is refluxed for 0.5 hour and then concentrated under vacuum.The residue is extracted with ether and the aqueous layer acidified with2N citric acid. The mixture is filtered and the solid washed with waterand dried (60° C. under vacuum) to give 1.61 g of crystals, m.p.210°-214° C.

EXAMPLE 484 N-(2-Methylphenyl)-4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)benzamide

A mixture of 0.332 g of 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.111 g oftriethylamine, 0.107 g of o-toluidine, and 0.15 ml of diethylphosphorylcyanide in 20 ml of dichloromethane is heated on a steam bath overnight.The mixture is washed with water, 1M NaHCO₃, 1N HCl, brine and dried(Na₂ SO₄). The dichloromethane solution is filtered through a thin padof hydrous magnesium silicate and the filtrate concentrated to dryness.The residue is crystallized from dichloromethane-hexane to give 0.23 gof white crystals, m.p. 228°-231° C.

EXAMPLE 485 N-(2,3-Dimethylphenyl)-4-(5H-pyrrolo 2,1-c!1,4!-benzodiazepin-10(11H)-ylcarbonyl)benzamide

A mixture of 0.332 g of 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.222 g oftriethylamine, 0.157 g of 2,3-dimethylaniline hydrochloride, 0.15 ml ofdiethylphosphoryl cyanide in 20 ml of dichloromethane is heated on asteam bath for 3 hours. The mixture is washed with H₂ O, 1M NaHCO₃, H₂O, 1N HCl, brine and dried (Na₂ SO₄). The solution is filtered through athin pad of hydrous magnesium silicate and the filter cake washed withdichloromethane. The filtrate is concentrated to dryness under vacuumand the residue crystallized from dichloromethane-hexane to give 0.11 gof crystals, m.p. 239°-240° C.

EXAMPLE 486 N- 4- (4,5-Dihydro-6H- 1,2,4!triazolo 4,3-a!1,5!benzodiazepin-6-yl)carbonyl)phenyl!-2-methylbenzoate

A mixture of 0.246 g of 4-(2-methylbenzoyl)amino!benzoyl chloride, 0.14g of 4,5-dihydro-6H- 1,2,4!triazolo 4,3-a! 1,5!benzodiazepine and 2 mlof pyridine is heated on a steam bath for 4.5 hours and heated (oilbath) at 110° C. overnight. The mixture is chilled and poured intowater. The mixture is neutralized with 1N HCl and filtered. The solid iswashed with dichloromethane and the dichloromethane filtrate evaporatedunder vacuum to give 0.151 g of product, MASS SPEC (FAB) 424.2(M+H).

EXAMPLE 487 N- 4-(Pyrrolo1,2-a!quinoxalin-5(4H)-ylcarbonyl)phenyl!-2,3-dichlorobenzamide

As described for Example 157, 0.47 g of4,5-dihydro-5-(4-aminobenzoyl)pyrrolo 1,2-a!quinoxaline, 346 μl oftriethylamine and 5 ml of dichloromethane are chilled (ice bath) and0.415 g of 2,3-dichlorobenzoyl chloride in 2 ml of dichloromethaneadded. After stirring overnight, an additional 346 μl of triethylamineis added and an additional 0.415 g of 2,3-dichlorobenzoyl chlorideadded. The mixture is stirred for 2 hours, diluted with 50 ml ofdichloromethane and the solution washed with 20 ml each of H₂ O, 2Ncitric acid, 1M NaHCO₃ and brine. The organic layer is dried (Na₂ SO₄)and filtered through a thin pad of hydrous magnesium silicate and thefiltrate concentrated to dryness. The residue is chromatographed onthick layer silica gel plates with ethyl acetate-hexane (1:1) as solventto give 0.100 g of white solid, m.p. 230°-240° C.

EXAMPLE 488 10- 4-(2-Chlorophenyl)sulfonyl!amino!benzoyl!-10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine

To a solution of 0,418 g of 2-chlorobenzenesulfonyl chloride in 5 ml ofdichloromethane, cooled to 0° C. is added 0.50 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineand 0.346 μl of triethylamine. The mixture is stirred at roomtemperature overnight and diluted with 50 ml of dichloromethane. Themixture is washed with 20 ml each of H₂ O, 2N citric acid, 1M NaHCO₃,brine and dried (Na₂ SO₄). The solution is filtered through a thin padof hydrous magnesium silicate and the filtrate concentrated to dryness.The residue is chromatographed on thick layer silica gel plates (4) withthe solvent ethyl acetate-hexane (1:1) to give a solid. Crystallizationfrom ethyl acetate gives 0.165 g of white crystals, m.p. 206°-210° C.

EXAMPLE 489 Methyl 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)benzoate

To a cooled solution of 0.50 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineand 346 μl of triethylamine in 5 ml of dichloromethane is added 0,394 gof mono methyl terephthaloyl chloride. The mixture is stirred overnightunder argon and diluted with 50 ml of dichloromethane. The mixture iswashed with 20 ml each of H₂ O, 2N citric acid, 1M NaHCO₃, brine anddried (Na₂ SO₄). The solution is filtered through a thin pad of hydrousmagnesium silicate and the filter cake washed with dichloromethane. Thefiltrate is concentrated to dryness and the residue crystallized fromethyl acetate to give 0.50 g of white crystals, m.p. 224°-228° C.

EXAMPLE 490 N- (Dimethylamino)methyl!-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2,4-dichlorobenzamide

To a suspension under argon of 0.072 g of sodium hydride (60% in oil) in10 ml of tetrahydrofuran is added 0.71 g of N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2,4-dichlorobenzamide andthe mixture stirred at room temperature for 1 hour. To the mixture isadded N,N-dimethylmethyleneammonium iodide and the mixture stirred 20hours. The mixture is diluted with diethyl ether (30 ml), filtered andthe filtrate concentrated under vacuum. The residue is triturated withhexane to give 0.76 g of white solid, m.p. 126°-129° C.

EXAMPLE 491 10- 4-(Diphenylphosphinyl)amino!benzoyl!-10,11-dihydro-5H-pyrrolo-2,1-c!1,4!benzodiazepine

A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine 0.060 g of triethylamine and 0.12 g ofdiphenylphosphinyl chloride in 2 ml of dichloromethane is stirred atroom temperature for 2 hours and then 1N NaOH is added. The mixture isextracted with ethyl acetate and the extract washed with brine and dried(Na₂ SO₄). The solvent is removed and the residue triturated withether-hexane to give 0.16 g of a white solid.

EXAMPLE 492 10- 4-Diphenoxyphosphinyl)amino!benzoyl!-10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine

To a solution of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine and 0.060 g of triethylamine in 2 ml ofdichloromethane is added 0.14 g of diphenoxyphosphinyl chloride. Themixture is stirred at room temperature for 2 hours and 1N NaOH added.The mixture is extracted with ethyl acetate and the extract washed withbrine and dried (Na₂ SO₄). The solvent is removed to give a solid.Trituration with ether-hexane gives 0.20 g of product as a white solid.

EXAMPLE 493 10- 4-(2,5-Dichlorophenyl)sulfonyl!amino!benzoyl!-10,11-dihydro-5H-pyrrolo2,1-c! 1,4!benzodiazepine

A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine, 0.050 g of triethylamine and 0.083 g of2,5-dichlorobenzenesulfonyl chloride in 2 ml of dichloromethane isstirred at room temperature for 1 hour and then 4 mg of4-(N,N-dimethylamino)pyridine is added. After another hour, 93 mg of2,5-dichlorobenzenesulfonyl chloride is added along with 50 mg oftriethylamine. The mixture is stirred at room temperature for 2 days and1N NaOH added. The mixture is extracted with ethyl acetate and theextract washed with 50% ammonium chloride solution, brine and dried (Na₂SO₄). The solvent is removed to give 0.30 g of solid. Trituration withether-hexane gives 0.26 g of solid. This solid is dissolved in a mixtureof 5 ml of tetrahydrofuran, 1 ml of methanol, 1 ml of 1N NaOH and themixture stirred for 18 hours at room temperature. The organic solventsare removed and the mixture extracted with ether acetate. The extract iswashed with NaHCO₃, brine and dried (Na₂ SO₄). The solvent is removedand the residue (0.16 g) triturated with ether to give 0.14 g of yellowsolid.

EXAMPLE 494 10- 4-(Phenylmethyl)sulfonyl!amino!benzoyl!-10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine

To a solution of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine and 0.060 g of triethylamine in 2 ml ofdichloromethane is added 0.10 g of α-toluenesulfonyl chloride. Themixture is stirred at room temperature for 2 hours and 1N NaOH is added.The mixture is extracted with ethyl acetate and the extract washed withbrine and dried (Na₂ SO₄). The solvent is removed and the residue (0.20g) is chromatographed on silica gel with the solvent ethylacetate-hexane (3:2) to give 0.080 g of product as a white solid and0.080 g of 10- 4-bis-(phenylmethyl)sulfonyl!amino!benzoyl!10,11-dihydro-5H-pyrrolo2,1-c!1,4!benzodiazepine as a white solid. The preceding compound in methanol,2N NaOH is heated on a steam bath, the solvent removed and the basicaqueous residue extracted with ethyl acetate to give an additionalamount of the product.

EXAMPLE 495 Ethyl 4- (2-methylbenzoyl)amino!-3-chlorobenzoate

A mixture of 8.26 g of ethyl 4-aminobenzoate, 8.26 g ofN-chlorosuccinimide in 50 ml of dichloromethane is refluxed overnight.The mixture is washed with saturated NaHCO₃ solution and dried (Na₂SO₄). The solution is passed through a thin pad of hydrous magnesiumsilicate and the filter cake washed with dichloromethane. The filtrateis concentrated and hexane added. Chilling gives 7.38 g of ethyl3-chloro-4-aminobenzoate, m.p. 82°-83° C.

To the preceding compound (3.66 g), 3.0 g of diisopropylethylamine in 50ml of dichloromethane is added 3.55 g of 2-methylbenzoyl chloride in 10ml of dichloromethane. The mixture is stirred at room temperatureovernight, washed with H₂ O, NaHCO₃ and dried (Na₂ SO₄). The solution ispassed through a thin pad of hydrous magnesium silicate and the filtercake washed with dichloromethane. The filtrate is concentrated anddiluted with hexane. Chilling gives 4.71 g of the product as crystals,129°-130° C.

The following Examples are prepared using the conditions of Example 495.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        496          Ethyl 4- (2-chlorobenzoyl!amino!-3-                                           chlorobenzoate                                                   497          Ethyl 4- (2,5-dichlorobenzoyl)amino!-                                         3-chlorobenzoate                                                 498          Ethyl 4- (2,4-dichlorobenzoyl)amino!-3-                                       chlorobenzoate                                                   499          Ethyl 4- (3,5-dichlorobenzoyl)amino!-3-                                       chlorobenzoate                                                   500          Ethyl 4- (2-methyl-4-chlorobenzoyl)-                                          amino!-3-chlorobenzoate                                          501          Ethyl 4- (2,3-dimethylbenzoyl)amino!-                                         3-chlorobenzoate                                                 502          Ethyl 4- (2-methoxybenzoyl)amino!-3-                                          chlorobenzoate                                                   503          Ethyl 4- (2-(trifluoromethoxy)benzoyl!-                                       amino!-3-chlorobenzoate                                          504          Ethyl 4- (2-methoxy-4-chlorobenzoyl)-                                         amino!-3-chlorobenzoate                                          505          Ethyl 4-  2-(methylthio)benzoyl!amino!-                                       3-chlorobenzoate                                                 506          Ethyl 4- (2-methylbenzeneacetyl!amino!-                                       3-chlorobenzoate                                                 507          Ethyl 4-  4-fluoro-2-(trifluoromethyl)-                                       benzoyl!amino!-3-chlorobenzoate                                  508          Ethyl 4-  4-fluoro-3-(trifluoromethyl)-                                       benzoyl!amino!-3-chlorobenzoate                                  509          Ethyl 4-  2-fluoro-3-(trifluoromethyl)-                                       benzoyl!amino!-3-chlorobenzoate                                  510          Ethyl 4- (2,3-dichlorobenzoyl)amino!-                                         3-chlorobenzoate                                                 511          Ethyl 4- (2,3-dichlorobenzoyl)amino!-                                         3-chlorobenzoate                                                 512          Ethyl 4- (4-fluoro-2-methylbenzoyl)-                                          amino!-3-chlorobenzoate                                          513          Ethyl 4- (5-fluoro-2-methylbenzoyl)-                                          amino!-3-chlorobenzoate                                          514          Ethyl 4-  2-fluoro-5-(trifluoromethyl)-                                       benzoyl!amino!-3-chlorobenzoate                                  515          Ethyl 4-  2-(trifluoromethyl)benzoyl!-                                        amino!-3-chlorobenzoate                                          516          Ethyl 4-  3-(trifluoromethyl)benzoyl!-                                        amino!-3-chlorobenzoate                                          ______________________________________                                    

EXAMPLE 517 N- 4-(4H-Pyrazolo 5,1-c!1,4!benzodiazepin-5(10H)-ylcarbonyl)phenyl!-3-fluoro-2-methylbenzamide

A solution of 2.87 g of 3-fluoro-2-methylbenzoic acid in 25 ml ofthionyl chloride is refluxed for 1.75 hour and the excess thionylchloride removed under vacuum. To the residue is added toluene (severaltimes) and the toluene removed under vacuum after each addition to give3-fluoro-2-methylbenzoyl chloride.

To a solution of 0.25 g of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo5,1-c! 1,4!benzodiazepine and 0.0914 g of triethylamine in 6 ml ofdichloromethane under argon is added a solution of 0.156 g of3-fluoro-2-methylbenzoyl chloride in 1.5 ml of dichloromethane. Themixture is stirred overnight at room temperature and is washed with H₂ Oand saturated NaHCO₃. The organic layer is treated with activated carbonand filtered through magnesium sulfate. The filtrate is evaporated,ethyl acetate added and the solvent removed to give 0.38 g of whitecrystals, m.p. 245°-250° C.: Exact mass by massspectrometry--441.1720(M+H).

EXAMPLE 518 N- 4-(4H-Pyrazolo 5,1-c!1,4!benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl!-5-fluoro-2-methylbenzamide

A mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo 5,1-c!1,4!benzodiazepine, 0.391 g of 4-(5-fluoro-2-methylbenzoyl)amino!-2-chlorobenzoyl chloride and 0.158 g ofdiisopropylethylamine in 10 ml of dichloromethane is stirred at roomtemperature overnight. The mixture is washed with H₂ O, 1N HCl, H₂ O, 1MNaHCO₃, brine and dried (Na₂ SO₄). The solution is passed through a thinpad of hydrous magnesium silicate and the filter cake washed withdichloromethane. The filtrate is again passed through a thin pad ofhydrous magnesium silicate. The filtrate is concentrated and the solidcrystallized from ethyl acetate to give crystals, m.p. 137°-140° C.

EXAMPLE 519 N- 4-(4H-Pyrazolo 5,1-c!1,4!benzodiazepin-5(10H)-ylcarbonyl!-3-chlorophenyl!-2-methylbenzamide

As described for Example 518, a mixture of 0.185 g of5,10-dihydro-4H-pyrazolo 5,1-c! 1,4!benzodiazepine, 0.369 g of 4-(2-methylbenzoyl)amino!-2-chlorobenzoyl chloride and 0.158 g ofdiisopropylethylamine in 10 ml of dichloromethane is stirred at roomtemperature to give crystals (from ethyl acetate) m.p. 241°-244° C.

EXAMPLE 520 N- 4-(4H-Pyrazolo 5,1-c!1,4!benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl!-2,4-dichlorobenzamide

As described for Example 518, a mixture of 0.185 g of5,10-dihydro-4H-pyrazolo 5,1-c! 1,4!benzodiazepine, 0.472 g of 4-(2,4-dichlorobenzoyl)amino!benzoyl chloride and 0.158 g ofdiisopropylethylamine in 10 ml of dichloromethane is stirred at roomtemperature overnight to give the product (0.27 g) as a pale yellowglass; anal. calc'd: C, 58.7; H, 3.4; N, 11.0; Cl, 20.8 Found C, 57.3;H, 3.3; N, 9.5; Cl, 21.3.

EXAMPLE 521 5,10-Dihydro-5-(4-nitro-2-chlorobenzoyl)-4H)-pyrazolo 5,1-c!1,4!benzodiazepine

To a solution of 1.85 g of 5,10-dihydro-4H-pyrazolo 5,1-c!1,4!benzodiazepine and 1.60 g of diisopropylethylamine in 50 ml ofdichloromethane, cooled in an ice bath, is added dropwise a solution of2.64 g of 4-nitro-2-chlorobenzoyl chloride in 25 ml of dichloromethane.The mixture is stirred at room temperature overnight and poured intowater. The organic layer is separated and washed with H₂ O, saturatedNaHCO₃, H₂ O and dried (Na₂ SO₄). The solution is passed through a thinpad of hydrous magnesium silicate and the filtrate evaporated. Theresidue is crystallized from dichloromethane-hexane to give 3.0 g ofcrystals, m.p. 197°-199° C.

EXAMPLE 522 5,10-Dihydro-5-(4-amino-2-chlorobenzoyl)-4H-pyrazolo 5,1-c!1,4!benzodiazepine

A mixture of 0.553 g of5,10-dihydro-5-(4-nitro-2-chlorobenzoyl)-4H-pyrazolo 5,1-c!1,4!benzodiazepine, 1.70 g of stannous chloride dihydrate in 20 ml ofethanol is heated at 70°-80° C. for 1 hour. The mixture is chilled, madebasic with 1M NaHCO₃ and then stirred at room temperature for 0.5 hour.The mixture is brought to pH 5 with acetic acid and extracted (severaltimes) with ethyl acetate. The combined extracts are dried (Na₂ SO₄) andpassed through a pad of hydrous magnesium silicate. The filtrate isevaporated and the residue dissolved in dichloromethane and the solutionpassed through a thin pad of hydrous magnesium silicate. The filtrate isevaporated in vacuo to give 0.40 g of a glass, m.p. 98°-117° C.; Anal.Calc'd: C, 62.9; H, 4.7; N, 16.3; Cl, 11.6. Found: C, 62.4; H, 4.3; N,15.6; Cl, 11.7.

The following examples are prepared using the conditions of Example 465.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        523          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl!-                                      2-fluorobenzamide, m.p. 223-226° C.                       524          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl!-                                      2-thiomethylbenzamide), white foam                               525          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl!-                                      2,3-dimethylbenzamide, m.p. 189-192° C.                   526          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl!-                                      2-chlorobenzamide, m.p. 198-203° C.                       527          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl!-                                      4-fluoro-2-chlorobenzamide, m.p.                                              139-141° C.                                               528          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl!-                                      2-(trifluoromethyl)benzamide, white foam                         529          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl!-                                      2,6-dichlorobenzamide, m.p. 246-248° C.                   ______________________________________                                    

EXAMPLE 530 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)-2-chlorophenyl!-2-methylbenzamide

To a mixture of 1.38 g of 10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 1.11 g of N,N-diisopropylethylamine in 50 ml ofdichloromethane is added 2.61 g of 4-(2-methylbenzoyl)amino!-3-chlorobenzoyl chloride in 25 ml ofdichloromethane. The mixture is stirred at room temperature overnightand then washed with H₂ O and saturated NaHCO₃. The organic layer isdried (Na₂ SO₄) and passed through a pad of hydrous magnesium silicate.The filtrate is concentrated, the residue (4.0 g) dissolved indichloromethane and again filtered through a pad of hydrous magnesiumsilicate. The filtrate is evaporated to give the product as a glass(3.62 g). A 1.8 g sample of the glass is crystallized from ethyl acetateto give 1.4 g of crystals, m.p. 176°-178° C.

The following Examples are prepared using the conditions of Example 530.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        531          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2,3-dimethylbenzamide                                            532          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2,5-dimethylbenzamide                                            533          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2,6-dimethylbenzamide                                            534          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-chlorobenzamide                                                535          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2,4-dichlorobenzamide                                            536          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2,5-dichlorobenzamide                                            537          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      3,5-dichlorobenzamide                                            538          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      3-fluorobenzamide, amorphous solid                               539          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-chloro-4-fluorobenzamide                                       540          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-methyl-4-chlorobenzamide                                       541          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-(methylthio)benzamide                                          542          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-chlorobenzeneacetamide                                         543          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-methylbenzeneacetamide                                         544          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-methylthiophene-3-carboxyamide                                 545          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      3-methylthiophene-2-carboxamide                                  546          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      3-fluoro-2-methylbenzamide,m.p. 230-                                          231° C.                                                   547          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      5-fluoro-2-methylbenzamide, m.p. 178-                                         180° C.                                                   548          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2,3-dichlorobenzamide                                            549          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2,3-difluorobenzamide                                            550          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      4-fluoro-2-methylbenzamide                                       551          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-methoxybenzamide                                               552          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-(trifluoromethoxy)benzamide                                    553          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-methoxy-4-chlorobenzamide                                      554          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-(trifluoromethyl)benzamide                                     555          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      3-(trifluoromethyl)benzamide                                     556          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2,6-dichlorobenzamide                                            557          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2,3,5-trichlorobenzamide                                         558          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-fluoro-05-(trifluoromethyl)benzamide                           559          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      4-fluoro-2-(trifluoromethyl)benzamide                            560          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2-fluoro-3-(trifluoromethyl)benzamide                            561          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-chlorophenyl!-                                      2,5-difluorobenzamide                                            562          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl!-5-fluoro-2-methylbenzamide                               563          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl!-2,3-dimethylbenzamide                                    564          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl!-3-fluoro-2-methylbenzamide                               565          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl!-2,4-dichlorobenzamide                                    566          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl!-2,3-dichlorobenzamide                                    567          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                         phenyl!-2-methylbenzamide                                        568          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-5-fluoro-2-methylbenzamide                               569          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-2,3-dimethylbenzamide                                    570          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-3-fluoro-2-methylbenzamide                               571          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-2,4-dichlorobenzamide                                    572          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-2,3-dichlorobenzamide                                    573          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-2-methylbenzamide                                        574          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-2,3-dichlorobenzamide                                    575          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-2,4-dichlorobenzamide                                    576          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-2-(methylthio)benzamide                                  577          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-2-chlorobenzamide                                        578          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-2-(trifluoromethyl)benzamide                             579          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                         phenyl!-2-(trifluoromethoxy)benzamide                            ______________________________________                                    

EXAMPLE 580 2,4-Dichloro-N- 4- (3-formyl-5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl)carbonyl!phenyl!benzamide

To a solution of 0.48 g of 2,4-dichloro-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl)carbonyl)phenyl!benzamide in 2 ml ofN,N-dimethylformamide at 0° C. is slowly added 0.3 ml of POCl₃. Themixture is stirred at 0° C. for 30 minutes and at room temperature for 1hour. The final mixture is quenched with ice and made alkaline with 2NNaOH to pH 12. The resulting precipitate is collected, washed with waterand dried in vacuo to give 0.55 g of solid. Further washing with 1:2ether-isopropanol gives 0.50 g of white solid. MS(CI)calculated503.0774; found 503.0789.

EXAMPLE 581 2,4-Dichloro-N- 4- 3-(hydroxymethyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl!carbonyl!phenyl!benzamide

To a suspension of 39 mg of NaBH₄ in 1 ml of tetrahydrofuran is added0.42 g of 2,4-dichloro-N- 4- (3-formyl-5H-pyrrolo 2,1-a!1,4!benzodiazepin-10 (11H)-yl)carbonyl!phenyl!benzamide and the reactionmixture stirred at room temperature for 18 hours and then quenched withwater. The tetrahydrofuran is evaporated in vacuo and the aqueousresidue treated with 5 ml of 1N NaOH and extracted with 50 ml of ethylacetate. The organic extract is washed with brine, dried over Na₂ SO₄and evaporated to give 0.47 g of a foam. Preparative thick layerchromatography by elution with 2:1 ethyl acetate-hexane gives 0.24 g ofwhite solid. MS(FAB): 488(MH⁺ --OH).

EXAMPLE 582 2,4-Dichloro-N- 4- 3-(1H-imidazol-1-ylmethyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepin-10(11H)-yl!carbonyl!phenyl!benzamide

To a suspension of 0.28 g of N,N-dimethylglycine hydrochloride in 5 mlof tetrahydrofuran is added 0.21 g of triethylamine and 0.35 g ofcarbonyldiimidazole. After stirring at room temperature for 30 minutesand then heating at reflux for 18 hours, the tetrahydrofuran isevaporated in vacuo to a residue which is dissolved in ethyl acetate andwashed with water, saturated NaHCO₃ and brine and dried over Na₂ SO₄,filtered and evaporated in vacuo to a residue. The residue is washedwith ether-hexanes (1:1) to give 0.17 g of white solid. MS(FAB):556(M+H).

EXAMPLE 583 α-Chloro-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide

To a solution of 0.61 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine in 8 ml of methylene chloride is added 0.30 gof triethylamine followed by 0.47 g of (±)-2-chloro-2-phenylacetylchloride in 2 ml of methylene chloride. The mixture is stirred at roomtemperature for 1 hour and then diluted with 10 ml of 50% NaHCO₃. Themethylene chloride is evaporated and the residue is extracted with ethylacetate. The separated organic layer is washed with saturated NaHCO₃ andbrine and then dried with Na₂ SO₄ followed by filtering through a pad ofhydrous magnesium silicate. The filtrate is evaporated to a residuewhich is stirred with ether-hexane to give 0.98 g of pink solid. MS(CI):456(M+H).

EXAMPLE 584 α- 2-(Dimethylamino)ethyl!thio!-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide

A mixture of 0.14 g of α-chloro-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide, 0.47 g of2-dimethylaminoethanethiol hydrochloride in 2 ml of methyl alcohol, 0.30g of triethylamine and 3 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is heated at 60° C.for 48 hours. The methyl alcohol is evaporated and the residue dilutedwith water. The resulting suspension is filtered and the precipitatewashed with water. The solid is dissolved in ethyl acetate and washedwith saturated NaHCO₃, brine and dried with Na₂ SO₄. The mixture isfiltered and the filtrate evaporated in vacuo to a residue which isstirred with ether-hexane to give 0.15 g of beige solid. MS(CI):525(M+H).

EXAMPLE 585 α- N-(Acetamido)amino!-N- 4-(5H-pyrrolo 2,1-c!1,4!-benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide

A mixture of 0.14 g of e-chloro-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide, 0.17 g ofglycinamide HCl, 0.15 g of triethylamine, 3 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 1 ml of methylalcohol is heated at 75° C. for 2 days. The methyl alcohol is evaporatedand the residue diluted with water. The resulting suspension is filteredand the precipitate washed with water. The solid is dissolved in ethylacetate and washed with saturated NaHCO₃, brine and dried with Na₂ SO₄.The mixture is filtered and the filtrate evaporated in vacuo to aresidue which is stirred with ether-hexanes to give 0.13 g of tan solid.MS(CI): 494(M+H).

EXAMPLE 586 α-(Dimethylamino)-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide

A partial solution of ?? g of α-chloro-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide in 1 ml ofmethanol is treated with 0.5 ml of dimethylamine and 1 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and stirringcontinued for 20 hours. The methanol is evaporated and the residuediluted with water. The resulting solid is washed with water, dissolvedin ethyl acetate and the organic layer washed with saturated NaHCO₃,brine and dried with Na₂ SO₄. The mixture is filtered and the filtrateevaporated in vacuo to give a residue which is stirred with ethylacetate-hexane to give 0.15 g of a beige solid. MS(CI): 465 (M+H).

EXAMPLE 587 α-(Acetyloxy)-N- 4-(5H-pyrrolo 2,1-c!1,4!-benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide

To a solution of 0.30 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine in 5 ml of methylene chloride is added 0.15 gof triethylamine followed by 0.27 g of O-acetylmandelic acid chloride.The mixture is stirred at room temperature for 1 hour and then dilutedwith 50% NaHCO₃. The methylene chloride is evaporated and the residue isextracted with ethyl acetate. The separated organic layer is washed withsaturated NaHCO₃ and brine and then dried with Na₂ SO₄ followed byfiltering through a pad of hydrous magnesium silicate. The filtrate isevaporated to a residue which is stirred with ether-hexane to give 0.54g of beige solid. MS(CI): 480(M+H).

EXAMPLE 588 (±)α-Hydroxy-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide

A solution of 0.34 g of α-(acetyloxy)-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!benzeneacetamide in 2 ml of1N NaOH and 4 ml of methyl alcohol is stirred at room temperature for 30minutes, diluted with 2 ml of water and evaporated in vacuo. The aqueoussuspension is extracted with 30 ml of ethyl acetate and the extractwashed with brine, dried with Na₂ SO₄ and filtered through a pad ofhydrous magnesium silicate and evaporated in vacuo to a residue. Theresidue is stirred with ether-hexanes to give 0.26 g of cream coloredsolid. MS(CI): 438(M+H).

EXAMPLE 589 2-Chloro-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!acetamide

To a stirred solution of 0.91 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!-benzodiazepinein 10 ml of methylene chloride is added 0.46 g of triethylamine and 36mg of dimethylaminopyridine followed by the slow addition of 0.42 g ofchloroacetyl chloride in 5 ml of methylene chloride. The resultingmixture is stirred at room temperature for 3 hours then partitioned with10 ml of 50% NaHCO₃ and the methylene chloride evaporated in vacuo. Theremaining suspension is filtered, washed with 50% NaHCO₃, H₂ O, EtOAc(2×2 ml), ether (2×5 ml) and dried in vacuo to give 1.14 g of beigesolid. MS(CI): 380(M+H).

EXAMPLE 590 N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-4-morpholineacetamide

A stirred suspension of 0.19 g of 2-chloro-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!acetamide in 1 ml ofmethylene chloride is added 0.44 g of morpholine followed by 1 ml of1,3-di-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and stirringcontinued for 20 hours. The methylene chloride is evaporated and theresidue diluted with water. The resulting suspension is filtered and theprecipitate washed with water. The brown solid is dissolved in 15 ml ofethyl acetate and washed with saturated NaHCO₃, brine and dried with Na₂SO₄. The mixture is filtered and the filtrate evaporated in vacuo togive 0.23 g of a colorless gum which is stirred with ethylacetate-hexanes to give 0.21 g of white solid. MS(CI): 431(M+H).

EXAMPLE 591 N- (2-Chlorophenyl)methyl!-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-4-morpholineacetamide

A mixture of 0.11 g of N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-4-morpholineacetamide, 56mg of O-chlorobenzyl bromide and 0.41 g of K₂ CO₃ in 5 ml ofacetonitrile is heated at reflux for 18 hours. An additional 30 mg ofO-chlorobenzyl bromide and 0.4 mmol of sodium hydride is added followedby heating for 24 hours. The reaction mixture is diluted with water andextracted with ethyl acetate. The organic layer is dried with Na₂ SO₄and evaporated to give 0.18 g of a residue which is purified bychromatography on silica gel with 1:1 ethyl acetate-methylene chlorideto give 80 mg of off white solid. MS(CI): 555 (M+H).

EXAMPLE 592 Ethyl 10- 4-(2,4-dichlorobenzoyl)amino!-3-methylbenzoyl!-10,11-dihydro-5H-pyrrolo2,1-c! 1,4!-benzodiazepine-3-carboxylate

To a solution of 0.30 g of ethyl10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine-3-carboxylate in 20 ml of methylene chloride is added0.15 g of N,N-diisopropylethylamine and 0.24 g of 2,4-dichlorobenzoylchloride. The reaction mixture is stirred at room temperature for 18hours and washed with water, saturated NaHCO₃ and dried with Na₂ SO₄.The organic layer is passed through a pad of hydrous magnesium silicate.Hexane is added to the filtrate at the boil to give 0.24 g of solid,m.p. 174°-184° C.

EXAMPLE 593 Methyl 10-4-(2,4-dichlorobenzoyl)amino!benzoyl!-10,11-dihydro-5H-pyrrolo2,1-c!1,4!benzodiazepine-3-carboxylate

To 50 ml of absolute methyl alcohol is added 0.15 g of sodium metal.After complete solution, 1.0 g of N- 4- 3-(trichloroacetyl)-5H-pyrrolo2,1-c!1,4!benzodiazepin-10(11H)-yl)!carbonyl!phenyl!-2,4-dichlorobenzamide isadded and the reaction mixture stirred overnight at room temperature.Methylene chloride is added followed by Na₂ SO₄. The organic layer isfiltered through hydrous magnesium silicate. Hexane is added at the boilto the filtrate to give 0.29 g of solid.

EXAMPLE 594 N- 4- 3-(trifluoroacetyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl)!carbonyl!phenyl!-2-(trifluoromethyl)benzamide

To a solution of 1.0 g of N- 4-(5H-pyrrolo 2,1-#!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-(trifluoromethyl)benzamidein 10 ml of methylene chloride is added 1.0 ml of trifluoroaceticanhydride followed by stirring for 18 hours at room temperature. Thereaction mixture is washed with saturated NaHCO₃, dried with Na₂ SO₄,filtered and hexane added at the boil to give a solid which iscrystallized from methylene chloride-hexane to give 0.89 g of solid,m.p. 248°-250° C.

EXAMPLE 595 N- 4- 3-(Trifluoroacetyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl!carbonyl!-3-chlorophenyl!-2-methylbenzamide

To a solution of 0.30 g of N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl!-2-methylbenzamidein 25 ml of methylene chloride is added 0.5 ml of trifluoroaceticanhydride followed by stirring at room temperature for 18 hours. Thereaction mixture is washed with saturated NaHCO₃, dried with Na₂ SO₄,filtered through hydrous magnesium silicate and hexane added to thefiltrate at the boil to give 0.22 g of colorless solid. MS: M+551.

EXAMPLE 596 Ethyl 10- 4-(2,4-dichlorobenzoyl)amino!benzoyl!-10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine-3-carboxylate

To 50 ml of absolute ethyl alcohol is added 0.30 g of sodium metal,followed by the addition of 2.0 g of N- 4-3-(trichloroacetyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)yl!carbonyl!phenyl!-2,4-dichlorobenzamideand-the mixture is stirred for 18 hours at room temperature. Thevolatiles are evaporated in vacuo to a residue which is dissolved inmethylene chloride and washed with H₂ O. The organic layer is dried withNa₂ SO₄ and filtered through hydrous magnesium silicate. Hexane is addedto the filtrate at the boil to give a solid which is crystallized frommethylene choloride-hexane to give 0.57 g of a solid. MS(M+):548.2.

EXAMPLE 597 N- 4- 3-(Trichloroacetyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl!carbonyl!phenyl!-2-(trifluoromethyl)benzamide

To a stirred solution of 0.48 g of N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-(trifluoromethyl)benzamidein 20 ml of methylene chloride is added 0.40 g of trichloroaceticanhydride followed by stirring at room temperature for 18 hours. Thereaction mixture is washed with water and saturated NaHCO₃, dried overNa₂ SO₄ and passed through a pad of hydrous magnesium silicate. Hexaneis added at the boil to give 0.37 g of solid, m.p. 219°-221° C.

EXAMPLE 598 N- 4- 3-(Trichloroacetyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl!carbonyl!phenyl!-2,4-dichlorobenzamide

To a stirred solution of 4.76 g of N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2,4-dichlorobenzamide in150 ml of methylene chloride is added 3.75 g of trichloroaceticanhydride followed by stirring for 18 hours. The reaction mixture iswashed with water and saturated NaHCO₃, dried over Na₂ SO₄ and passedthrough a pad of hydrous magnesium silicate. The filtrate is evaporatedin vacuo to give 2.91 g of solid.

EXAMPLE 599 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2,3,5-trichlorobenzamide

As described for Example 8, 0.50 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis reacted with 0.483 g of 2,3,5-trichlorobenzoyl chloride to give aglass which is crystallized from ethyl acetate to give 0.686 g ofcrystals, m.p. 231°-234° C.

EXAMPLE 600 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!tetrahydrofurane-2-carboxamide

As described for Example 8, 0.500 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepineis reacted with 0.267 g of tetrahydrofurane-2-carbonyl chloride to givea glass which is crystallized from ethyl acetate to give 0.22 g ofcrystals, m.p. 208°-214° C.

The following Examples are prepared using conditions of Example 297 withthe appropriately substituted aroyl chloride.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        601          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2,5-                                        dichlorophenyl!-2,3-dimethylbenzamide                            602          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2,5-                                        dichlorophenyl!-2-chlorobenzamide                                603          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2,5-                                        dichlorophenyl!-2,4-dichlorobenzamide                            604          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2,5-                                        dichlorophenyl!-3,5-dichlorobenzamide                            605          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2,5-                                        dichlorophenyl!-2-methyl-4-chloro-                                            benzamide                                                        606          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2-methoxybenzamide                                 607          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2-(trifluoromethoxy)                                            benzamide                                                        608          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2-(trifluoromethyl)                                             benzamide                                                        609          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2,4-dichlorobenzamide,                                          amorphous white solid, m.p. 134-137° C.                   610          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2-(methylthio)benzamide                            611          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-3-fluoro-2-methyl-                                              benzamide, amorphous white solid,                                             m.p. 136-138° C.                                          612          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-5-fluoro-2-methyl-                                              benzamide, amorphous solid, m.p.                                              132-135° C.                                               613          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-4-fluoro-2-methyl-                                              benzamide                                                        614          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-4-fluoro-2-(trifluoro-                                          methyl)benzamide                                                 615          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!--2,3-dichlorobenzamide                             616          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2,3-difluorobenzamide                              617          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2-fluoro-5-(trifluoro-                                          methyl)benzamide                                                 618          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2-fluoro-3-(trifluoro-                                          methyl)benzamide                                                 619          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-4-fluoro-2-(trifluoro-                                          methyl)benzamide                                                 620          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2,5-difluorobenzamide                              621          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2,3-difluorobenzamide                              622          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2,5-dimethylbenzamide                              623          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-3-methyl-2-thiophene-                                           carboxamide                                                      624          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2-methyl-3-thiophene-                                           carboxamide                                                      625          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2-methyl-3-furane-                                              carboxamide                                                      626          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-3-methyl-2-furane-                                              carboxamide                                                      627          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2-chlorobenzeneacetamide                           628          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-2-methylbenzeneacetamide                           629          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          chlorophenyl!-4-fluoro-3-(trifluoro-                                          methyl)benzamide                                                 630          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-3-fluoro-2-methyl)-                                             benzamide                                                        631          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2,3-dichlorobenzamide                              632          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2,3-difluorobenzamide                              633          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-4-fluoro-2-methyl-                                              benzamide                                                        634          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-5-fluoro-2-methyl-                                              benzamide                                                        635          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2-fluoro-5-(trifluoro-                                          methyl)benzamide                                                 636          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2-methylbenzamide                                  637          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2-chlorobenzamide                                  638          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2,3-dimethylbenzamide                              639          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2,5-dimethylbenzamide                              640          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-methoxybenzamide                                   641          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2-(trifluoromethoxy)-                                           benzamide                                                        642          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2-methoxy-4-chloro-                                             benzamide                                                        643          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2,6-dichlorobenzamide                              644          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2-(methylthio)benzamide                            645          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2-(trifluoromethyl)-                                            benzamide                                                        646          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-3-(trifluoromethyl)-                                            benzamide                                                        647          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-2-                                          chlorophenyl!-2,3,5-trichlorobenzamide                           648          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-3-fluoro-2-methylbenz-                                         amide                                                            649          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-5-fluoro-2-methylbenz-                                         amide                                                            650          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-4-fluoro-2-methylbenz-                                         amide                                                            651          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-2,4-dichlorobenzamide                             652          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-2,3-dimethylbeznamide                             653          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-3-fluoro-5-(trifluoro-                                         methyl)benzamide                                                 654          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-3-fluoro-2-methylbenz-                                         amide                                                            655          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-5-fluoro-2-methylbenz-                                         amide                                                            656          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-4-fluoro-2-methylbenz-                                         amide                                                            657          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-2,4-dichlorobenzamide                             658          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-2,3-dimethylbenzamide                             659          N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!-                                          1,5!benzodiazepin-5-yl)carbonyl!-3-                                          methoxyphenyl!-3-fluoro-5-(trifluoro-                                         methyl)benzamide                                                 ______________________________________                                    

EXAMPLE 660 N- 4- 3- - (Dimethylamino)methyl!-5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl!carbonyl!phenyl!-2-methylbenzamide

To a stirred solution of 0,842 g of 2-methyl-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-yl-carbonyl)phenyl!benzamide in 25 ml of 1:1methanoltetrahydrofuran is added 10 ml of 35% formaldehyde and ml of 30%N,N-dimethylamine at 0° C. After 2 drops of acetic acid is added, thereaction mixture is stirred at room temperature for 16 hours. Thereaction mixture is concentrated in vacuo to a residue which isdissolved in chloroform and washed with water. The organic layer isdried with Na₂ SO₄ and evaporated in vacuo to a residue. The residue ischromatographed on silica gel with 10:1 ethyl acetate-methanol as eluentto give 0.800 g of the desired product, M⁺ H: 479.

The following products are prepared by using the condition of Example660 and by using the appropriately substituted benzamide.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        661          N- 4-  3-(1-piperidinylmethyl)-5H-                                            pyrrolo 2,1-c! 1,3!benzodiazepin-                                             10(11H)-yl!carbonyl!phenyl!-2-methyl-                                         benzamide, solid; mass spectrum (M.sup.+ H)                                   518                                                              662          N- 4-  3-(4-morpholinomethyl)-5H-                                             pyrrolo 2,1-c! 1,3!benzodiazepin-                                             10(11H)-yl!carbonyl!phenyl!-2-methyl-                                         benzamide, solid; mass spectrum (M.sup.+ H)                                   521                                                              663          N- 4-  3-  4-(phenylmethyl)-1-pipera-                                         zinyl!methyl!-5H-pyrrolo 2,1-c! 1,4!-                                         benzodiazepin-10(11H-yl!carbonyl!-                                            phenyl!-2-methylbenzamide, solid; mass                                        spectrum (M.sup.+ H) 610                                         664          N- 4-  3- (dimethylaminomethyl!-                                              5H-pyrrolo 2,1-c! 1,4!benzodiazepin-                                          10(11H)-yl!carbonyl!phenyl!-2,4-di-                                           chlorobenzamide, solid; mass spectrum                                         (M.sup.+ H) 535                                                  665          N- 4-  3-(1-pyrrolidinylmethyl)-                                              5H-pyrrolo 2,1-c! 1,4!benzodiazepin-                                          10(11H)-yl!carbonyl!phenyl!-2,4-di-                                           chlorobenzamide, solid; mass spectrum                                         (M.sup.+ H) 561                                                  666          N- 4-  3-(4-morpholinomethyl)-5H-                                             pyrrolo 2,1-c! 1,4!benzodiazepin-                                             10(11H)-yl!carbonyl!phenyl!-2,4-di-                                           chlorobenzamide, solid; mass spectrum                                         (M.sup.+ H) 576                                                  667          N- 4-  3- (diethylamino)methyl!-5H-                                           pyrrolo 2,1-c! 1,4!benzodiazepin-                                             10(11H)-yl!carbonyl!phenyl!-2,4-di-                                           chlorobenzamide, solid; mass spectrum                                         (M.sup.+ H) 562                                                  668          N- 4-  3- (dimethylamino)methyl!-5H-                                          pyrrolo 2,1-c! 1,4!benzodiazepin-                                             10(11H)-yl!carbonyl!-3-chlorophenyl!-                                         5-fluoro-2-methylbenzamide, solid;                                            mass spectrum (M.sup.+ H) 531                                    669          N- 4-  3- (dimethylamino)methyl!-5H-                                          pyrrolo 2,1-c! 1,4!benzodiazepin-                                             10(11H)-yl!carbonyl!-3-chlorophenyl!-                                         2-methylbenzamide, solid; mass spectrum                                       (M.sup.+ H) 513                                                  ______________________________________                                    

EXAMPLE 670 N- 4- (3-Acetyl-5H-pyrrolo 2,1-c!1,4!benzodiazepin-(11H)-yl!carbonyl!phenyl!-2,4-dichlorobenzamide

A stirred solution of 0.954 g of N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2,4-dichlorobenzamide in 25ml of methylene chloride and 5 ml of acetic anhydride is heated atreflux for 24 hours. The volatiles are evaporated in vacuo to a residuewhich is purified by column chromatography on silica gel by elution withethyl acetatehexane (7:3) to give 0,800 g of a white solid; massspectrum (M+H)519.

EXAMPLE 671 1-2-Nitro-5-(ethoxycarbonyl)benzyl!-pyrrole-2-carboxaldehyde

To a stirred slurry of 2.2 g of sodium hydride (60% in oil, washed withhexane) in tetrahydrofuran is added at 0° C. a solution of 4.5 g ofpyrrole-2-carboxaldehyde in 25 ml of tetrahydrofuran. After the additionis complete, a solution of 15 g of ethyl 4-nitro-3-bromomethylbenzoatein 30 ml of dry tetrahydrofuran is slowly added under nitrogen. Thereaction mixture is stirred at 20° C. for 8 hours and carefully quenchedwith water. The reaction mixture is extracted with chloroform which iswashed with water, dried with Na₂ SO₄ and concentrated in vacuo to give12 g of the desired product as a solid; mass spectrum (M⁺ H)349.

EXAMPLE 672 1-2-Nitro-4-(ethoxycarbonyl)benzyl!-pyrrole-2-carboxaldehyde

The conditions of Example 671 are used with ethyl3-nitro-4-bromomethylbenzoate to give 13.0 g of the desired product as asolid; mass spectrum (M⁺ H)349.

EXAMPLE 673 Ethyl 10,11-Dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine-7-carboxylate

A solution of 10.0 g of 1-2-nitro-5-(ethoxycarbonyl)benzyl!-pyrrole-2-carboxaldehyde in 150 ml ofabsolute ethanol containing 1.0 g of 10% Pd/c is hydrogenated in a Parrapparatus for 16 hours under 40 psi of hydrogen. The reaction mixture isfiltered through a pad of diatomaceous earth and the filtrateconcentrated in vacuo to a residue of 5.5 g of the desired product as asolid; mass spectrum (M⁺ H)255.

EXAMPLE 674 Ethyl 10,11-Dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine-8-carboxylate

The hydrogenation conditions of Example 673 are used with 1-2-nitro-4-(ethoxycarbonyl)benzyl!pyrrole-2-carboxaldehyde to give 5.0 gof the desired product as a solid; mass spectrum (M⁺ H)255.

EXAMPLE 675 Ethyl 10,11-Dihydro-10- 4-(2-methylbenzoyl)amino!benzoyl!-5H-pyrrolo 2,1-c!1,4!benzodiazepine-7-carboxylate

A solution of 1.2 g of ethyl 10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine-7-carboxylate in 100 ml of methylene chloride iscooled to 0° C. and 10 ml of triethylamine added followed by 1.5 g of 4-(2-methylbenzoyl)amino)benzoyl chloride. The reaction mixture is stirredat room temperature for 18 hours and concentrated in vacuo to a residuewhich is partitioned between water and chloroform. The organic layer isdried over Na₂ SO₄ and concentrated in vacuo to a residue. The residueis purified by column chromatography on silica gel by elution with 40%ethyl acetatehexane to give 1.0 g of the desired product as a solid;mass spectrum (M⁺ H)494.

EXAMPLE 676 Ethyl 10,11-Dihydro-10- 4-(2-methylbenzoyl)amino!benzoyl!-5H-pyrrolo 2,1-c!1,4!benzodiazepin-8-carboxylate

The conditions of Example 675 are used with ethyl10,11-dihydro-5H-pyrrolo 2,1-c! 1,4!benzodiazepine-8-carboxylate to give1.2 g of the desired product as a solid; mass spectrum (M⁺ H)494.

The subject compounds of the present invention are tested for biologicalactivity as follows:

EXAMPLE 677 10,11-Dihydro-10-(4-nitrobenzoyl)-5H-imidazo 2,1-c!1,4!benzodiazepine

A 292 mg sample of sodium hydride in oil is washed, under argon, withpentane. The residue is diluted with 17 ml of dioxane and then 1.35 g of10,11-dihydro-5H-imidazo 2,1-c! 1,4!benzodiazepine is added. Thereaction mixture is warmed slightly until the hydrogen evolution ceases.To the cooled reaction mixture is added a solution of 1.36 g ofp-nitrobenzoyl chloride in 45 ml of dioxane and the mixture is stirredat room temperature for 18 hours. The solvent is evaporated in vacuo andthe residue is heated with CHCl₃, filtered hot and the filter cakewashed with hot CHCl₃. The combined CHCl₃ layers are washed with water,saturated NaHCO₃, treated with activated charcoal, filtered through apad of MgSO₄ and the filtrate evaporated in vacuo to give 1.82 g ofbrown solid residue. The residue is purified by flash chromatography byelution with CHCl₃ --MeOH to give 630 mg of the desired product as asolid. HR FABMS:(M+H)=335.3433.

EXAMPLE 678 10,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo 2,1-c!1,4!benzodiazepine

A mixture of 0.550 g of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo2,1-c! 1,4!benzodiazepine and 1.86 g of SnCl₂.2H₂ O in 22 ml of ethylalcohol is refluxed for 1 hour under argon. The mixture is diluted withwater and then a solution of 10% NaHCO₃ is added until the reactionmixture is basic. Additional ethyl alcohol is added and reaction mixtureevaporated in vacuo to give a residue which is triturated with 1:1 CHCl₃--CH₃₀ H several times and filtered. The filtrates are combined, treatedwith activated carbon and filtered through diatomaceous earth. Thefiltrate is evaporated in vacuo to give 680 mg of tan crystalline solid.The solid is stirred in ethanol, water and 10% NaHCO₃ to pH=8, for 5hours and extracted with CHCl₃ three times. The combined extracts aretreated with activated carbon, filtered through MgSO₄ and evaporated invacuo to give 370 mg of tan crystalline solid. CIMS(CH₄): MH⁺ =305.

EXAMPLE 679 N- 4-(5H-Imidazo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2,4-dichlorobenzamide

A slurry of 0.330 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo2,1-c! 1,4!benzodiazepine in 15 ml of dioxane is stirred and warmedslightly to obtain a nearly complete solution. The reaction mixture iscooled to room temperature and 43 mg of sodium hydride in oil added. Themixture is warmed slightly. Gas evolution stops in a few minutes. Thereaction mixture is cooled to room temperature and 153 μl of2,4-dichlorobenzoyl chloride in 2.5 ml of dioxane added. An additional3.5 ml of dioxane is added and the reaction mixture stirred at roomtemperature for 2 days. The volatiles are evaporated in vacuo to aresidue which is partitioned between water and chloroform. The organiclayer is separated and the aqueous phase extracted with chloroform twomore times. The combined organic layers are trated with activated carbonand filtered through MgSO₄. The filtrate is evaporated in vacuo to a tanfoam which is purified by flash chromatography on silica gel by elutionwith CHCl₃ and 3-7% CH₃ OH in chloroform to give 310 mg of tan foam.

EXAMPLE 680 6,7-Dihydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo 1,2-a!1,5!benzodiazepin

To a solution of 0.28 g of 6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepine in 6 ml of methylene chloride is added 0.30 g oftriethylamine followed by 0.50 g of 2-chloro-4-nitrobenzoyl chloride in0.5 ml of methylene chloride. The reaction mixture is stirred at roomtemperature for 1 hour then quenched with 5 ml of saturated NaHCO₃. Themethylene chloride is evaporated in vacuo and the residue is dilutedwith 5 ml of water and extracted with 20 ml of ethyl acetate. Theorganic layer is separated washed with saturated NaHCO₃ and brine, driedwith Na₂ SO₄ and evaporated in vacuo to give 0.59 g of a yellow foamwhich is triturated with ether-hexanes to give 0.56 g of the desiredproduct as off-white solid. MS(CI): 368(M+H)(Cl³⁵) 370 (M+H) (Cl³⁷)

EXAMPLE 681 6,7-Dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo 1,2-a!1,5!benzodiazepine

To a solution of 0,50 g of6,7-dihydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo 1,2-a!1,5!benzodiazepine in 10 ml of ethyl alcohol and 2 ml of tetrahydrofuranis added 2.35 g of SnCl₂.2H₂ O and the mixture stirred at 55° C. for 30minutes. The solvents are evaporated in vacuo to a residue which isstirred with 20 ml of 1N NaOH and 40 ml of ethyl acetate for 15 minutesand filtered through diatomaceous earth. The filter pad is washed with2×10 ml of ethyl acetate and the combined extracts washed with brine,dried (Na₂ SO₄) and evaporated in vacuo to give 0.47 g of solid residuewhich is triturated with ether-hexane to give 0.43 g of light yellowcrystalline solid. MS(CI): 338 (M+H, Cl³⁵) 340 (M+H, Cl³⁷)

EXAMPLE 682 N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-3-fluoro-2-methylbenzamide

To a mixture of 0.10 g of6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo- 1,2-a!1,5!benzodiazepine and 0.06 g of triethylamine in 6 ml ofdichloromethane is added 0.08 g of 3-fluoro-2-methylbenzoyl chloride in0.5 ml of dichloromethane. The mixture is stirred for 2 hours at roomtemperature and then 2 ml of 1N NaOH added. The volatiles are evaporatedunder vacuum and the residue dissolved in 2 ml of tetrahydrofuran and 1ml of methanol. The mixture is stirred for 2 hours and evaporated andthe residue diluted with 2 ml of i N NaOH and 5 ml of water. The mixtureis extracted with ethyl acetate (15 ml) and the extract washed withbrine and dried (Na₂ SO₄). The solvent is removed and the residuetriturated with diethyl ether-hexane to give 0.15 g of white solid: MassSpectrum (CI)474(M+H, Cl³⁵); 476(M+H, Cl³⁷).

EXAMPLE 683 N- 4- (6,7-Dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,4-dichlorobenzamide

To a mixture of 0.10 g of6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo 1,2-a!1,5!benzodiazepine and 0.06 g of triethylamine in 6 ml ofdichloromethane is added 0.10 g of 2,4-dichlorobenzoyl chloride in 0.5ml of dichloromethane. The mixture is stirred at room temperature for 2hours and 2 ml of 1N NaOH is added. The volatiles are removed undervacuum and to the residue is added 2 ml of tetrahydrofuran and 1 ml ofmethanol. The mixture is stirred at room temperature for 2 hours and thevolatiles removed. To the residue is added 2 ml of 1N NaOH and 5 ml ofH₂ O. The mixture is extracted with ethyl acetate and the extract washedwith brine and dried (Na₂ SO₄). The solvent is removed and the solidtriturated with diethyl ether-hexane to give 0.15 g of white solid, MassSpectrum (CI): 510(M+H, Cl³⁵).

EXAMPLE 684 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-(1H-1,2,4!-triazol-1-yl)acetamide

To a suspension of 0.20 g of 1,2,4-triazole sodium in 1 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is added 0.10 g of2-chloro-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!acetamide in 1 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone followed by stirringat room temperature for 3 hours. The reaction mixture is quenched with15 ml of water and the resulting solid is collected, washed with waterand hexanes to give 70 mg of the desired product as a tan solid. MS(CI):413 (M+H).

EXAMPLE 685 N- 4-(5H-Pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!-2-(2-formyl-1-pyrrolo)acetamide

To a suspension of 72 mg of sodium hydride (60% in oil) in 5 ml oftetrahydrofuran is added 0.14 g of pyrrole-2-carboxaldehyde. The mixtureis stirred for 1 hour at room temperature and 94 mg of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 0.19 g of2-chloro-N- 4-(5H-pyrrolo 2,1-c!1,4!benzodiazepin-10(11H)-ylcarbonyl)phenyl!acetamide added. The mixtureis stirred at room temperature, water added and the tetrahydrofuranevaporated in vacuo. The resulting suspension is filtered and theprecipitate washed with water and hexanes. The collected solid ispurified by column chromatography on silica gel by elution with 3:2ethyl acetate-hexanes to give 50 mg of pink solid. MS(CI): 439(M+H).

EXAMPLE 686 N- 4-(3-Chloro-4H-pyrazolo 5,1-c!1,4!benzodiazepin-5-(10H)-ylcarbonyl)phenyl!-2-methyl-5-fluorobenzamide

A mixture of 356 mg of N- 4H-pyrazolo 5,1-c!1,4!benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl!-5-fluoro-2-methylbenzamideand 122 mg of N-chlorosuccinimide in 5 ml of methylene chloride isrefluxed on a steam bath for 3 hours. The reaction mixture is washedwith saturated NaHCO₃, H₂ O and brine, then dried over Na₂ SO₄ andpassed through a pad of hydrous magnesium silicate. The filtrate isevaporated in vacuo to give 190 mg of the desired product as a solid.

The following examples are prepared using the conditions of Example 465.

    ______________________________________                                        Example No.  Compound                                                         ______________________________________                                        687          N 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl!-2-bromo-                                       benzamide, white solid                                           688          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-2-                                             (acetoxy)benzamide, light yellow solid                           689          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-2-                                             hydroxybenzamide, light yellow solid                             690          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-1-                                             naphthylcarboxamide, white solid                                 691          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-methylphenyl!-                                      2-methylbenzamide, amorphous solid                               692          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-2-chloro-                                      4-fluorobenzamide, white foam                                    693          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-2-(tri-                                        fluoromethyl)-4-fluorobenzamide, white                                        solid                                                            694          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-methylphenyl!-                                      5-fluoro-2-methylbenzamide, m.p. 180-                                         182° C.                                                   695          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-methoxy-                                            phenyl!-5-fluoro-2-methylbenzamide,                                           amorphous solid                                                  696          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl!-2-fluoro-4-(trifluoromethyl)                                          benzamide, m.p. 140-154° C.                               697          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl!-2-methylbenzeneacetamide,                                             white glass                                                      698          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl!-2-fluoro-6-(trifluoromethyl)                                          benzamide, white solid, m.p. 150-230° C.                  699          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl!-2-fluoro-3-(trifluoromethyl)                                          benzamide, white glass                                           700          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl!-2-chloro-5-(methylthio)                                               benzamide, white crystals, m.p.                                               124-134° C.                                               701          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl!-2,5-dimethylbenzamide,                                                crystalline solid, m.p. 253-255° C.                       702          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chloro-                                             phenyl!-2-chloro-3,4-dimethoxybenzamide,                                      yellow foam                                                      703          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-6-chloro-3-                                           methoxyphenyl!-2-methylbenzamide,                                             crystals, m.p. 214-215° C.                                704          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-2-methoxy                                             phenyl!-2,5-dimethylbenzamide,                                                crystals, m.p. 174-175° C.                                705          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-2-chloro-                                      3,4-dimethoxybenzamide, white crystals,                                       m.p. 242-244° C.                                          706          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)phenyl!-2,5-                                           dimethylbenzamide, crystals,                                                  m.p. 158-160° C.                                          707          N- 4-(5H-pyrrolo 2,1-c! 1,4!benzodiaze-                                       pin-10(11H)-ylcarbonyl)-3-chlorophenyl!-                                      2-(trifluoromethyl)-4-fluorobenzamide,                                        white glass                                                      ______________________________________                                    

EXAMPLE 708 Methyl 4-2-(2-chlorophenyl)-2-cyano-2-(4-morpholinyl)ethyl!benzoate

A 0.876 g sample of 60% sodium hydride in oil is washed with hexanefollowed by the addition of 60 ml of dry N,N-dimethylformamide. Thereaction mixture is stirred for 1 hour under argon at room temperatureafter the addition of 4.73 g ofα-(2-chlorophenyl)-4-morpholineacetonitrile. To the reaction mixture isadded 4.58 g of methyl 4-(bromomethyl)benzoate and stirring continuedfor 3 hours. Several drops of acetic acid is added to ice water and thereaction quenched. The pH is 3-4 and saturated NaHCO₃ added to adjustthe pH to 6-7. Upon cooling a solid forms which is filtered, washed withwater and dried to give 5.92 g of yellow solid. Crystallization frommethylene chloride-hexane gives 2.10 g of the desired product as acrystalline solid, m.p. 116°-118° C.

EXAMPLE 709 Methyl 4- 2-(2-chlorophenyl)-2-oxoethyl!benzoate

A mixture of 1.0 g of methyl4-(2-chlorophenyl)-2-cyano-2-(4-morpholinyl)ethyl!benzoate and 14 ml ofwater is heated at reflux for 20 minutes then poured over crushed ice.After stirring for 15 minutes the resulting solid is collected, washedwith water and air dried to give 0.63 g of tan solid, m.p. 40°-42° C.

EXAMPLE 710 4- 2-(2-Chlorophenyl)-2-oxoethyl!benzoic acid

A mixture of 18.78 g of methyl 4- 2-(2-chlorophenyl)-2-oxoethyl!benzoatein 288.8 ml of CH₃ OH, 72.2 ml of water and 5.2 g of NaOH is refluxedfor 3 hours then acidified with 2N citric acid. The reaction mixture isevaporated in vacuo to remove the CH₃ OH. The aqueous phase is extractedwith CH₂ Cl₂ and acidified with 1N HCl. The resulting solid is collectedand dried under vacuum to give 17.27 g of the desired product, m.p.168°-172° C.

EXAMPLE 711 3-Methoxy-4-nitrobenzoyl chloride

A stirred suspension of 1.0 g of 3-methoxy-4-nitrobenzoic acid and 1.40ml of thionyl chloride is heated to reflux for 2 hours. The mixture iscooled to room temperature, 2 ml of iso-octane added and the mixtureevaporated in vacuo to a solid residue. The residue is washed withiso-octane (2×2 ml), dried in vacuo to give 1.08 g of cream coloredsolid.

EXAMPLE 712 10,11-Dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine

To a solution of 0.55 g of 10,11-dihydro-5H-pyrrolo 2,1-c!1,4!benzodiazepine in 8 ml of methylene chloride is added 0.55 g oftriethylamine followed by 0.97 g of 3-methoxy-4-nitrobenzoyl chloride.The reaction mixture is stirred at room temperature for 2 hours and thenquenched with 10 ml of 1N NaOH. The methylene chloride layer isevaporated and the resulting suspension filtered. The precipitate iswashed with 1N NaOH (2×5 ml), water (3×5 ml) and hexane (2×5 ml). Thecollected solid is dried in vacuo to give 1.13 g of off-white solid.MS(CI): 364(M+H).

EXAMPLE 713 10;11-Dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo2,1-c! 1,4!benzodiazepine

A mixture of 0.91 g of10,11-dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine, 4.51 g of SnCl₂.2H₂ O, 6 ml of ethyl alcohol, 6 mlof tetrahydrofuran and 16 ml of methylene chloride is stirred at 50° C.for 2 hours. The solvents are evaporated in vacuo and the residuedissolved in 80 ml of ethyl acetate. The solution is treated with 50 mlof 1N NaOH with stirring for 30 minutes. The resulting suspension isfiltered through diatomaceous earth. The pad is washed with ethylacetate (3×15 ml). The combined ethyl acetate solutions are washed withbrine, dried (Na₂ SO₄), filtered through hydrous magnesium silicate andevaporated in vacuo to 0.99 g of residue which is stirred withether-hexanes to give 0.90 g of cream colored solid. MS(CI): 334(M+H).

EXAMPLE 714 10,11-Dihydro-10- 4-(3-methylpropyloxycarbonyl)amino!benzoyl!-5H-pyrrolo 2,1-c!1,4!benzodiazepine

To a stirred solution of 0.15 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepinein 2 ml of methylene chloride is added 0.10 g of triethylamine followedby 0.10 g of isobutylchloroformate. The reaction mixture is stirred for3 hours and then quenched with 1N NaOH. The organic layer is evaporatedin vacuo to a residue which is stirred in 5 ml of tetrahydrofuran for 1hour, then evaporated in vacuo to a residue. The residue is extractedwith ethyl acetate-methylene chloride, washed with brine, dried (Na₂SO₄), filtered through hydrous magnesium silicate and evaporated invacuo to give a residue which is stirred with ethyl acetate-methylenechloride to give 0.22 g of cream colored solid. MS(CI): 404 (M+H).

EXAMPLE 715 10,11-Dihydro-10- 4-(pentanoyl)aminobenzoyl)!-5H-pyrrolo2,1-c! 1,4!benzodiazepine

To a stirred solution of 0.15 g of10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo 2,1-c! 1,4!benzodiazepinein 2 ml of methylene chloride is added 0.10 g of triethylamine followedby 0.09 g of valeryl chloride. The reaction mixture is stirred for 3hours and then quenched with 4 ml of 1N NaOH. The methylene chloride isevaporated in vacuo and the residue dissolved in 5 ml of tetrahydrofuranfor 1 hour and evaporated in vacuo to a residue. The residue isextracted with ethyl acetate-methylene chloride, washed with brine andthe organic layer dried (Na₂ SO₄), filtered through hydrous magnesiumsilicate, and evaporated in vacuo to give 0.23 g of a residue which isstirred with ether-hexanes to give 0.19 g of a white solid. MS(CI): 388(M+H).

EXAMPLE 716 10,11-Dihydro-10- 4-3-methylbutanoyl)amino!benzoyl!-5H-pyrrolo 2,1-c! 1,4!benzodiazepine

To a stirred solution of 0.10 g of10,11-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine in 1 ml of methylene chloride is added 0.06 g oftriethylamine followed by 0.05 g of iso-valeryl chloride. The reactionmixture is stirred for 3 hours and then quenched with 1N NaOH. Theorganic layer is evaporated in vacuo to a residue which is stirred in 5ml of tetrahydrofuran for 1 hour, then evaporated in vacuo to a residue.The residue is extracted with ethyl acetate-methylene chloride, washedwith brine, dried (Na₂ SO₄), filtered through hydrous magnesium silicateand evaporated in vacuo to give 0.15 g of residue which is stirred withether-hexane to give 0.13 g of light yellow solid. MS(CI): 418(M+H).

EXAMPLE 717 10,11-Dihydro-10- 3-methoxy-4-(butylsulfonyl)amino!benzoyl!-5H-pyrrolo 2,1-c! 1,4!benzodiazepine

To a stirred solution of 0.10 g of10,11-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo 2,1-c!1,4!benzodiazepine in 2 ml of methylene chloride is added 60 mg oftriethylamine followed by a solution of 56 mg of n-butylsulfonylchloride in 0.5 ml of methylene chloride. After stirring at roomtemperature for 2 hours, the reaction mixture is evaporated in vacuo toa residue which is dissolved in methyl alcohol, stirred for 1 hour andevaporated in vacuo to a residue which is treated with 2 ml of NH₄ Cland extracted with 15 ml of ethyl acetate. The organic extract is washedwith saturated NaHCO₃, brine, dried (Na₂ SO₄), filtered through hydrousmagnesium silicate and the filtrate evaporated to a residue. The residueis stirred with ether-hexanes to give 0.14 g of light yellow solid.MS(CI): 454 (M+H).

UTILITY TESTING

Binding Assay to Rat Hepatic V₁ Receptors

Rat liver plasma membranes expressing the vasopressin V₁ receptorsubtypes are isolated by sucrose density gradient according to themethod described by Lesko et al., (1973). These membranes are quicklysuspended in 50.0 mM Tris. HCl buffer, pH 7.4, containing 0.2% bovineserum albumin (BSA) and 0.1 mM phenylmethylsulfonylfluoride (PMSF) andkept frozen at -70° C. until used in subsequent binding experiments. Forbinding experiments, the following is added to the wells of a ninety-sixwell format microtiter plate: 100 μl of 100.0 mM Tris.HCl buffercontaining 10.0 mM MgCl₂, 0.2% heat inactivated BSA and a mixture ofprotease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %;1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mMPMSF, 20.0 μl of phenylalanyl-3,4,5,-3H! vasopressin (S.A. 45.1Ci/mmole) at 0.8 nM, and the reaction initiated by the addition of 80 μlof tissue membranes containing 20 μg of tissue protein. The plates arekept undisturbed on the bench top at room temperature for 120 min. toreach equilibrium. Non-specific samples are assayed in the presence of0.1 μM of the unlabeled antagonist phenylalanylvasopressin, added in20.0 μl volume.

For test compounds, these are solubilized in 50% dimethylsulfoxide(DMSO) and added in 20.0 μl volume to a final incubation volume of 200μl. Upon completion of binding, the content of each well is filteredoff, using a Brandel® cell Harvester (Gaithersburg, Md.). Theradioactivity trapped on the filter disk by the ligand-receptor complexis assessed by liquid scintillation counting in a Packard LS Counter,with an efficiency of 65% for tritium. The data are analyzed for IC₅₀values by the LUNDON-2 program for competition (LUNDON SOFTWARE, OH).

Binding Assay to Rat Kidney Medullary V₂ Receptors

Medullary tissues from rat kidneys are dissected out, cut into smallpieces and soaked in a 0.154 mM sodium chloride solution containing 1.0mM EDTA with many changes of the liquid phase, until the solution isclear of blood. The tissue is homogenized in a 0.25M sucrose solutioncontaining 1.0 mM EDTA and 0.1 mM PMSF using a Potter-Elvehjemhomogenizer with a teflon pestle. The homogenate is filtered throughseveral layers (4 layers) of cheese cloth. The filtrate is rehomogenizedusing a dounce homogenizer, with a tight fitting pestle. The finalhomogenate is centrifuged at 1500×g for 15 min. The nuclear pellet isdiscarded and the supernatant fluid recentrifuged at 40,000×g for 30min. The resulting pellet formed contains a dark inner part with theexterior, slightly pink. The pink outer part is suspended in a smallamount of 50.0 mM Tris.HCl buffer, pH 7.4. The protein content isdetermined by the Lowry's method (Lowry et al., J. Biol. Chem., 1953).The membrane suspension is stored at -70° C., in 50.0 mM Tris.HCl,containing 0.2% inactivated BSA and 0.1 mM PMSF in aliquots of 1.0 mlcontaining 10.0 mg protein per ml of suspension until use in subsequentbinding experiments.

For binding experiments, the following is added in μl volume to wells ofa 96 well format of a microtiter plate: 100.0 μl of 100.0 mM Tris.HClbuffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl₂ and a mixtureof protease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %;1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mMPMSF, 20.0 μl of ³ H!Arginine⁸, vasopressin (S.A. 75.0 Ci/mmole) at 0.8nM and the reaction initiated by the addition of 80.0 μl of tissuemembranes (200.0 μg tissue protein). The plates are left undisturbed onthe bench top for 120 min to reach equilibrium. Non-specific binding isassessed in the presence of 1.0 μM of unlabeled ligand, added in 20 μlvolume. For test compounds, these are solubilized in 50%dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a finalincubation volume of 200 μl. Upon completion of binding, the content ofeach well is filtered off, using a Brandel® cell Harvester(Gaithersburg, Md.). The radioactivity trapped on the filter disk by theligand-receptor complex is assessed by liquid scintillation counting ina Packard LS Counter, with an efficiency of 65% for tritium. The dataare analyzed for IC₅₀ values by the LUNDON-2 program for competition(LUNDON SOFTWARE, OH). The results of this test on representativecompounds of this invention are shown in Table XIII.

Radioligand Binding Experiments with Human Platelet Membranes

(a) Platelet Membrane Preparation

Frozen platelet rich plasma (PRP), (Platelet Source: Hudson Valley BloodServices, Westchester Medical Center, Valhalla, N.Y.) are thawed to roomtemperature. The tubes containing the PRP are centrifuged at 16,000×gfor 10 min. at 4° C. and the supernatant fluid discarded. The plateletsresuspended in an equal volume of 50.0 mM Tris.HCl, pH 7.5 containing120 mM NaCl and 20.0 mM EDTA. The suspension is recentrifuged at16,000×g for 10 min. This washing step is repeated one more time. Thewash discarded and the lysed pellets homogenized in low ionic strengthbuffer of Tris.HCl, 5.0 mM, pH 7.5 containing 5.0 mM EDTA. Thehomogenate is centrifuged at 39,000×g for 10 min. The resulting pelletis resuspended in Tris.HCl buffer, 70.0 mM, pH 7.5 and recentrifuged at39,000×g for 10 min. The final pellet is resuspended in 50.0 mM Tris.HClbuffer pH 7.4 containing 120 mM NaCl and 5.0 mM KCl to give 1.0-2.0 mgprotein per ml of suspension.

(b) Binding to Vasopressin V₁ receptor subtype in Human PlateletMembranes

In wells of a 96 well format microtiter plate, add 100 μl of 50.0mMTris.HCl buffer containing 0.2% BSA and a mixture of proteaseinhibitors (aprotinin, leupeptin etc.). Then add 20 μl of ³ H!Ligand(Manning or Arg⁸ Vasopressin), to give final concentrations ranging from0.01 to 10.0 nM. Initiate the binding by adding 80.0 μl of plateletsuspension (approx. 100 μg protein). Mix all reagents by pipetting themixture up and down a few times. Non specific binding is measured in thepresence of 1.0 μM of unlabeled ligand (Manning or Arg⁸ Vasopressin).Let the mixture stand undisturbed at room temperature for ninety (90)min. Upon this time, rapidly filter off the incubate under vacuumsuction over GF/B filters, using a Brandel Harvester. Determine theradioactivity caught on the filter disks by the addition of liquidscintillant and counting in a liquid scintillator.

Binding to Membranes of Mouse Fibroblast Cell Line (LV-2) Transfectedwith the cDNA Expressing the Human V₂ Vasopressin Receptor

(a) Membrane Preparation

Flasks of 175 ml capacity, containing attached cells grown toconfluence, are cleared of culture medium by aspiration. The flaskscontaining the attached cells are rinsed with 2×5 ml of phosphatebuffered saline (PBS) and the liquid aspirated off each time. Finally, 5ml of an enzyme free dissociation Hank's based solution (SpecialtyMedia, Inc., Lafayette, N.J.) is added and the flasks are leftundisturbed for 2 min. The content of all flasks is poured into acentrifuge tube and the cells pelleted at 300×g for 15 min. The Hank'sbased solution is aspirated off and the cells homogenized with apolytron at setting #6 for 10 sec in 10.0 mM Tris.HCl buffer, pH 7.4containing 0.25M sucrose and 1.0 mM EDTA. The homogenate is centrifugedat 1500×g for 10 min to remove ghost membranes. The supernatant fluid iscentrifuged at 100,000×g for 60 min to pellet the receptor protein. Uponcompletion, the pellet is resuspended in a small volume of 50.0 mMTris.HCl buffer, pH 7.4. The protein content is determined by the Lowrymethod and the receptor membranes are suspended in 50.0 mM Tris.HClbuffer containing 0.1 mM phenylmethylsulfonylfluoride (PMSF) and 0.2%bovine serum albumin (BSA) to give 2.5 mg receptor protein per ml ofsuspension.

(b) Receptor Binding

For binding experiments, the following is added in μl volume to wells ofa 96 well format of a microtiter plate: 100.0 μl of 100.0 mM Tris.HClbuffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl₂ and a mixtureof protease inhibitors: leupeptin, 1.0 mg%; aprotinin, 1.0 mg %;1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mMPMSF., 20.0 μl of ³ H!Arginine⁸, vasopressin (S.A. 75.0 Ci/mmole) at 0.8nM and the reaction initiated by the addition of 80.0 μl of tissuemembranes (200.0 μg tissue protein). The plates are left undisturbed onthe bench top for 120 min to reach equilibrium. Non specific binding isassessed in the presence of 1.0 μM of unlabeled ligand, added in 20 μlvolume. For test compounds, these are solubilized in 50%dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a finalincubation volume of 200 μl. Upon completion of binding, the content ofeach well is filtered off, using a Brandel® cell Harvester(Gaithersburg, Md.). The radioactivity trapped on the filter disk by theligand-receptor complex is assessed by liquid scintillation counting ina Packard LS Counter, with an efficiency of 65% for tritium. The dataare analyzed for IC₅₀ values by the LUNDON-2 program for competition(LUNDON SOFTWARE, OH).

                                      TABLE XIII                                  __________________________________________________________________________    Binding Assay to Rat Hepatic V.sub.1 Receptors and Rat Kidney Medullary       V.sub.2 Receptors or                                                          *Binding to V.sub.1 Receptor Subtype in Human Platelet and **Binding to       Membranes of Mouse Fibroblast                                                 Cell Line (LV-2) Transfected with the cDNA Expressing the Human V.sub.2       Receptor                                                                                                           V.sub.1                                                                              V.sub.2                           Ex. No.                                                                            Structure                       IC.sub.50 (μM)                                                                    IC.sub.50 (μM)                 __________________________________________________________________________          ##STR154##                     0.097  0.029                             215                                                                                 ##STR155##                     0.016  0.022                             3                                                                                   ##STR156##                     0.038  0.004                             4                                                                                   ##STR157##                     0.12   0.014                             5                                                                                   ##STR158##                     0.015  0.025                             6                                                                                   ##STR159##                     0.023  0.003                             7                                                                                   ##STR160##                     0.01   0.005                             8                                                                                   ##STR161##                     0.056  0.035                             14                                                                                  ##STR162##                     0.17   0.066                             40                                                                                  ##STR163##                     2.4    0.12                              41                                                                                  ##STR164##                     0.037  0.017                             82                                                                                  ##STR165##                     (10 μM) 23%                                                                       (10 μM) 71%                    84                                                                                  ##STR166##                     0.045  0.077                             85                                                                                  ##STR167##                     0.009  0.013                             87                                                                                  ##STR168##                     (10 μM) 63%                                                                       (10 μM) 80%                    89                                                                                  ##STR169##                     0.023  0.008                             91                                                                                  ##STR170##                     0.026  0.022                             93                                                                                  ##STR171##                     0.0009 0.0007                            96                                                                                  ##STR172##                     0.056  0.011                             116                                                                                 ##STR173##                     0.28   0.085                             117                                                                                 ##STR174##                     2.77   0.377                             354                                                                                 ##STR175##                     0.012  0.007                             355                                                                                 ##STR176##                     0.165  0.35                              356                                                                                 ##STR177##                     0.087  0.053                             357                                                                                 ##STR178##                     0.019  0.017                             358                                                                                 ##STR179##                     0.011  0.016                             384                                                                                 ##STR180##                     0.188  0.059                             2                                                                                   ##STR181##                     0.031  0.014                             9                                                                                   ##STR182##                     0.007  0.004                             17 160                                                                              ##STR183##                     1.2    0.11                              21                                                                                  ##STR184##                     0.93   0.087                             36 179                                                                              ##STR185##                     0.10   0.054                             54                                                                                  ##STR186##                     0.31*  0.007**                           99                                                                                  ##STR187##                     0.027  0.010                             210 214                                                                             ##STR188##                     0.058  0.016                             217                                                                                 ##STR189##                     0.068 0.19*                                                                          0.005 0.01**                      267 271                                                                             ##STR190##                     0.22   0.028                             274                                                                                 ##STR191##                     0.24*  0.031**                           297 298                                                                             ##STR192##                     0.27   0.033                             465                                                                                 ##STR193##                     0.020* 0.0015**                          466                                                                                 ##STR194##                     0.026  0.004                             467                                                                                 ##STR195##                     0.031  0.005                             468                                                                                 ##STR196##                     0.027  0.029                             469                                                                                 ##STR197##                     0.094  0.015                             470                                                                                 ##STR198##                     0.054  0.0045                            471                                                                                 ##STR199##                     0.045  0.0083                            472                                                                                 ##STR200##                     0.89   (10 μM) 22%                    473                                                                                 ##STR201##                     (10 μM) 90%                                                                       (10 μM) 56%                    474                                                                                 ##STR202##                     0.087  0.038                             476                                                                                 ##STR203##                     0.084  0.069                             477                                                                                 ##STR204##                     0.003* 0.0032**                          478                                                                                 ##STR205##                     0.032* 0.0019**                          479                                                                                 ##STR206##                     0.023* 0.008                             480                                                                                 ##STR207##                     0.54*  0.026**                           481                                                                                 ##STR208##                     1.0    0.0034                            482                                                                                 ##STR209##                     0.41   0.0023                            484                                                                                 ##STR210##                     0.097  0.025                             485                                                                                 ##STR211##                     0.24   0.013                             486                                                                                 ##STR212##                     (10 μM) 39%                                                                       (10 μM) 77%                    488                                                                                 ##STR213##                     (10 μM) 96%                                                                       (10 μM) 87%                    489                                                                                 ##STR214##                     (10 μM) 61%                                                                       (10 μM) 82%                    490                                                                                 ##STR215##                     0.014  0.005                             491                                                                                 ##STR216##                     (10 μM) 82%                                                                       (10 μM) 83%                    492                                                                                 ##STR217##                     0.16   3.2                               493                                                                                 ##STR218##                     0.14   (10 μM) 68%                    494                                                                                 ##STR219##                     0.11   5.8                               517                                                                                 ##STR220##                     0.21   0.015                             518                                                                                 ##STR221##                     0.22*  0.0017**                          519                                                                                 ##STR222##                     0.12*  0.0032**                          520                                                                                 ##STR223##                     0.85*  0.0044**                          523                                                                                 ##STR224##                     0.11*  0.0028**                          524                                                                                 ##STR225##                     0.17*  0.0012**                          525                                                                                 ##STR226##                     0.43*  0.00042**                         526                                                                                 ##STR227##                     0.05*  0.0033**                          527                                                                                 ##STR228##                     0.026* 0.00067**                         528                                                                                 ##STR229##                     0.20*  0.006**                           538                                                                                 ##STR230##                     0.052* 0.001**                           546                                                                                 ##STR231##                     0.066* 0.073**                           547                                                                                 ##STR232##                     0.016* 0.004**                           529                                                                                 ##STR233##                     0.99*  0.002**                           530                                                                                 ##STR234##                     0.003* 0.0037                            580                                                                                 ##STR235##                     0.2    0.08                              581                                                                                 ##STR236##                     0.021  0.0053                            582                                                                                 ##STR237##                     0.13   0.014                             583                                                                                 ##STR238##                     0.054  0.027                             584                                                                                 ##STR239##                     1.2    0.48                              585                                                                                 ##STR240##                     0.28   0.083                             586                                                                                 ##STR241##                     0.45   0.23                              587                                                                                 ##STR242##                     0.067  0.022                             588                                                                                 ##STR243##                     0.040  0.012                             589                                                                                 ##STR244##                     (10 μM) 91%                                                                       (10 μM) 82%                    590                                                                                 ##STR245##                     (10 μM) 89%                                                                       (10 μM) 81%                    591                                                                                 ##STR246##                     (10 μM) 45%                                                                       (10 μM) 64%                    592                                                                                 ##STR247##                     3.3    0.24                              593                                                                                 ##STR248##                     0.21   0.042                             594                                                                                 ##STR249##                     (10 μM) 78%                                                                       (10 μM) 23%                    595                                                                                 ##STR250##                     (10 μM) 57%                                                                       (10 μM) 93%                    687                                                                                 ##STR251##                     0.002* 0.007**                           597                                                                                 ##STR252##                     (10 μM) 100%                                                                      (10 μM) 97%                    598                                                                                 ##STR253##                     (10 μM) 58%                                                                       (10 μM) 93%                    599                                                                                 ##STR254##                     0.046  0.014                             600                                                                                 ##STR255##                     0.42   0.74                              609                                                                                 ##STR256##                     2.4*   0.021**                           611                                                                                 ##STR257##                     0.5*   0.004**                           660                                                                                 ##STR258##                     0.073  0.064                             661                                                                                 ##STR259##                     0.057  0.057                             662                                                                                 ##STR260##                     0.04   0.035                             663                                                                                 ##STR261##                     0.009  0.025                             664                                                                                 ##STR262##                     0.12   0.048                             665                                                                                 ##STR263##                     0.056  0.039                             666                                                                                 ##STR264##                     0.16   0.013                             667                                                                                 ##STR265##                     0.17   0.013                             668                                                                                 ##STR266##                     0.17*  0.029**                           669                                                                                 ##STR267##                     0.071* 0.035**                           689                                                                                 ##STR268##                     0.085* 0.54**                            676                                                                                 ##STR269##                     (10 μM) 41%                                                                       (10 μM) 89%                    670                                                                                 ##STR270##                     1.1    0.29                              685                                                                                 ##STR271##                     0.061* 0.061**                           612                                                                                 ##STR272##                     1.7*   0.01**                            688                                                                                 ##STR273##                     0.069* 0.034**                           690                                                                                 ##STR274##                     0.22*  0.022**                           691                                                                                 ##STR275##                     0.072* 0.0029**                          692                                                                                 ##STR276##                     0.007* 0.004**                           693                                                                                 ##STR277##                     0.021* 0.005**                           694                                                                                 ##STR278##                     0.12   0.0017**                          695                                                                                 ##STR279##                     0.015* 0.0018**                          696                                                                                 ##STR280##                     12.4*  0.065**                           697                                                                                 ##STR281##                     0.62*  0.003**                           698                                                                                 ##STR282##                     1.3*   0.013**                           699                                                                                 ##STR283##                     (1 μM) 19%                                                                        (1 μM) 100%                    700                                                                                 ##STR284##                     (1 μM) 77%*                                                                       (10 μM) 100%**                 701                                                                                 ##STR285##                     0.34*  (1 μM) 100%                    702                                                                                 ##STR286##                     (1 μM) 9%*                                                                        (1 μM) 85%**                   703                                                                                 ##STR287##                     (1 μM) 35%*                                                                       (1 μM) 87%**                   704                                                                                 ##STR288##                     (1 μM) 100%*                                                                      (1 μM) 92%**                   707                                                                                 ##STR289##                     0.20*  0.006**                           714                                                                                 ##STR290##                     0.023* 0.041**                           715                                                                                 ##STR291##                     0.0078*                                                                              0.073**                           716                                                                                 ##STR292##                     0.002* 0.031**                           __________________________________________________________________________

Vasopressin V₂ Antagonist Activity in Conscious Hydrated Rats

Conscious hydrated rats are treated with compounds under study from 0.1to 100 mg/kg orally or vehicle. Two to four rats are used for eachcompound. One hour later, arginine vasopressin (AVP, antidiuretichormore, ADH) dissolved in peanut oil is administered at 0.4 μg/kgintraperitoneally. Two rats in each test would not receive argininevasopressin but only the vehicle (peanut oil) to serve as water-loadingcontrol. Twenty minutes later each rat is given 30 mL/kg of deionizedwater orally by gavage and is placed individually in a metabolic cageequipped with a funnel and a graduated glass cylinder to collect urinefor four hours. Urine volume is measured and osmolality analyzed by useof a Fiske One-Ten osmometer (Fiske Assoc., Norwood, Mass., USA).Urinary sodium, potassium, and chloride are analyzed by use ofion-specific electrodes in a Beckman E3 (Electrolyte 3) Analyzer.

In the following results, decreased urine volume and decreasedosmolality relative to AVP-control indicates activity. The results ofthis test on representative compounds of this invention are shown inTable XIV.

                  TABLE XIV                                                       ______________________________________                                        Vasopressin V.sub.2 Antagonist Activity In                                    Conscious Hydrated Rats                                                                Dose             Urine Volume                                                                            Osmolality                                Ex. No.  (mg/kg) N        (ml/4 hrs)                                                                              (mOsm/kg)                                 ______________________________________                                        *                78       13.3 ± 0.3                                                                            229 ± 6                               **               6        12.1 ± 1                                                                              497 ± 53                                               4        12.4 ± 0.8                                                                            361 ± 30                              ***              76        2 ± 0.2                                                                             1226 ± 58                              1        30      2         1.1      1504                                      215      30      2         0.7      1520                                      3        10      7        15.8 ± 1                                                                              567 ± 33                                        3      8         9.6 ± 0.9                                                                            584 ± 56                                        1      5         6.5 ± 1                                                                              515 ± 79                              4        10      2        16.9       571                                                3      4         9.5 ± 1.2                                                                            646 ± 115                                       1      2         2        1129                                      5        30      2         7.7       955                                               10      2         8.5      1079                                      6        30      5        17.9 ± 1.3                                                                            616 ± 87                                       10      8        20.4 ± 1.1                                                                            346 ± 25                                        3      4        15 ± 1.6                                                                              519 ± 30                                        1      2         6         970                                      7        30      2        12.4       815                                               10      2         9         780                                      8        30      2         9.1      1010                                               10      2         3.4      1211                                      14       10      2         5.2       836                                                3      2         4.5      1000                                      82       30      2         1.7      1808                                      84       30      2         6.5       425                                               10      2         4.4       416                                      85       30      2        12.5       383                                               10      2         2        1123                                      87       20      2         4.3      1300                                               10      2         3        1488                                      89       30      2         3.3      1320                                      91       10      2        12.5       414                                                3      2         2.3      1267                                      93       30      2         5.1       594                                      96       10      4        10.3 ± 1.3                                                                            647 ± 63                                        3      2         4.4       716                                      116      30      2         8        1295                                               10      2         5.5      1242                                      354      10      2         8.8      1010                                      356      10      2         5.8      1023                                      358      30      1         5.5       875                                      2        10      2         9.3      1015                                      9        10      2         5.8       702                                      99       30      2        15.2       334                                      467      10      2        18         365                                      466      10      2        14.1       522                                      17,160   30      2        4.1       1374                                      489      10      2         6.1      1194                                      490      10      4        71.5 ± 1.6                                                                            487 ± 38                              590      10      2         3        1355                                      581      10      4         4 ± 1.2                                                                              941 ± 219                             469      10      2        11.3       548                                      599      10      2        18         407                                      470      10      3        17         387                                      471      10      4        14.1 ± 1.9                                                                            507 ± 38                              479      10      2         6        1042                                      482      10      4        22 ± 0.9                                                                              372 ± 17                              54       10      2         5        1275                                      274      10      2         3        1177                                      465      10      2        21.8       361                                      480      10      2         8.8       827                                      528      10      2        11.3       647                                      529      10      2        10.5       569                                      520      10      2        18.5       394                                      519      10      2        19.9       399                                      523      10      2         5        1218                                      524      10      2        10         528                                      525      10      2        13         557                                      526      10      2        17.8       455                                      527      10      2        19.5       430                                      530      10      2         6         914                                      518      10      2        17.5       363                                      668      10      2        20.7       378                                      609                                                                           611                                                                           472      10      2         4.3      1453                                      582      10      2         9.5       604                                      473      10      2         2.3      1493                                      474      10      2        11.5       619                                      594      10      4         4.9 ± 1.2                                                                           1172 ± 182                             586      10      2         4.3      1196                                      584      10      2         2.4      1718                                      595      10      2         8.3      1474                                      588      10      2         9.5       687                                      587      10      2         9         868                                      210,214  10      2        15.2       451                                      597      10      2         5.3      1250                                      517      10      2        14.7       411                                      217      10      2        14.3       466                                      585      10      2         3.3      1483                                      476      10      2         5        1233                                      593      10      2        11.8       577                                      596      10      2         2.8      1347                                      297 (298)                                                                              10      2         7         796                                      477      10      2         5.3       701                                      478      10      3         3        1399                                      267,271                                                                       592                                                                           ______________________________________                                         *Water-load control                                                           **Waterload Control + DMSO (10%) (20%)                                        ***AVPcontrol                                                            

Vasopressin V₁ Antagonist Activity in Conscious Rats

Conscious rats are restrained in a supine position with elastic tape.The area at the base of the tail is locally anesthetized by subcutaneousinfiltration with 2% procaine (0.2 ml). Using aseptic technique theventral caudal tail artery is isolated and a cannula made of PE 10 and20 (heat-fused) tubing is passed into the lower abdominal aorta. Thecannula is secured, heparinized (1000 i.u./cc), sealed and the woundclosed with one or two stitches of Dexon 4-0. The caudal vein is alsocannulated in the same manner for intravenous drug administration. Theduration of the surgery is approximately 5 minutes. Additional localanesthesia (2% procaine or lidocaine) is provided as needed.

The animals are placed in plastic restraining cages in an uprightposition. The cannula is attached to a Statham P23Db pressure transducerand pulsatile blood pressure is recorded. Increase of systolic bloodpressure responses to arginine vasopressin 0.01 and 0.2 internationalunit (I.U.)(350 I.U.=1 mg) injections are recorded prior to any drug(compound) administration, after which each rat is dosed orally withcompounds under study 0.1-100 mg/kg (10 cc/kg) or intravenously 0.1-30mg/kg (1 cc/kg). The vasopressin injections are repeated30,60,90,120,180,240 and 300 min. later. Percentage of antagonism by thecompound is calculated using the pre-drug vasopressin vasopressorresponse as 100%.

The results of this test on representative compounds of this inventionare shown in Table XV.

The results of this test on representative compounds of this inventionin which the dose, the maximum % inhibition and the time in minutes, areshown in Table XVI.

                                      TABLE XV                                    __________________________________________________________________________    VASOPRESSIN (VAS) VASOPRESSOR RESPONSE                                                  VAS Dose                                                            Dose      i.u./kg                                                                            Min Post                                                                           Control                                                                             Response Average                                                                           %                                      (mg/kg)   I.V. Dose Before VAS                                                                          After VAS                                                                          Change                                                                            Change                                                                            Inhibition                             __________________________________________________________________________    CONTROL   0.01  0   155   188  33  33.5                                                           156   190  34                                                       0.02      153   213  60  52.5                                                           165   210  45                                             Ex. No. 1                                                                           10 i.v.                                                                           0.01  30  161   165   4  4   88                                                         170   174  4                                                        0.02      159   170  11  8   85                                                         167   172   5                                                       0.01  60  157   173  16  16.5                                                                              51                                                         164   181  17                                                       0.02      157   182  25  20  62                                                         178   193  15                                                       0.01  90  151   176  25  21  37                                                         159   176  17                                                       0.02      154   184  30  27  49                                                         165   189  24                                                       0.01 120  159   173  23  22.5                                                                              33                                                         157   179  22                                                       0.02      150   191  41  37.5                                                                              29                                                         162   196  34                                                       0.01 180  148   177  29  29  13                                                         155   184  29                                                       0.02      151   209  58  48   9                                                         165   203  38                                                       0.01 240  146   176  30  27  19                                                         151   175  24                                                       0.02      151   200  49  39.5                                                                              25                                                         162   192  30                                                       0.01 300  146   176  30  32   4                                                         151   185  34                                                       0.02      151   200  49  39.5                                                                              25                                                         162   192  30                                             SPONTANEOUSLY HYPERTENSIVE RATS n= 2 Body weight(s): 400,480 grams            CONTROL   0.01  0   131   168  37  31                                                             167   192  25                                                       0.02      131   190  59  50                                                             173   214  41                                             Ex. No. 2                                                                           10 i.v.                                                                           0.01  30  127   135   8  6.5 79                                                         175   180   5                                                       0.02      135   144   9  8   84                                                         178   185   7                                                       0.01  60  137   144   7  8   74                                                         172   181   9                                                       0.02      135   145  10  13  74                                                         176   192  16                                                       0.01  90  124   138  14  10.5                                                                              66                                                         173   180   7                                                       0.02      132   147  15  15  70                                                         173   188  15                                                       0.01 120  135   143   8  9.5 69                                                         167   178  11                                                       0.02      134   150  16  15  70                                                         170   184  14                                                       0.01 180  124   142  18  14  55                                                         165   175  10                                                       0.02      129   150  21  22  56                                                         162   185  23                                                       0.01 240  125   144  19  16.5                                                                              47                                                         164   178  14                                                       0.02      133   158  25  25  50                                                         167   192  25                                                       0.01 300  127   145  18  17.5                                                                              44                                                         159   176  17                                                       0.02      134   170  36  31.5                                                                              37                                                         163   190  27                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 430,480 grams           CONTROL   0.01  0   175   215  40  50                                                             175   235  60                                                       0.02      185   240  55  55                                                             200   255  55                                             Ex. No. 3                                                                            3 i.v.                                                                           0.01  30  180   190  10  15  70                                                         175   195  20                                                       0.02      180   205  25  23.5                                                                              57                                                         185   207  22                                                       0.01  60  185   190   5  12.5                                                                              75                                                         180   200  20                                                       0.02      185   195  10  17.5                                                                              68                                                         185   210  25                                                       0.01  90  175   185  10  17.5                                                                              65                                                         175   200  25                                                       0.02      185   195  10  15  73                                                         185   205  20                                                       0.01 120  170   185  15  20  60                                                         175   200  25                                                       0.02      175   200  25  32.5                                                                              41                                                         185   225  40                                                       0.01 180  175   195  20  30  40                                                         165   205  40                                                       0.02      180   235  55  55   0                                                         185   240  55                                                       0.01 240  165   195  30  40  20                                                         160   210  50                                                       0.02      180   225  45  52.5                                                                               5                                                         185   245  60                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 340,330 grams           CONTROL   0.01  0   170   215  45  53.5                                                           163   225  62                                                       0.02      185   225  40  52.5                                                           190   255  65                                             Ex. No. 3                                                                           30 p.o.                                                                           0.01  30  170   180  10  15  72                                                         155   175  20                                                       0.02      175   190  15  20  62                                                         160   185  25                                                       0.01  60  165   190  25  22.5                                                                              57                                                         150   170  20                                                       0.02      170   190  20  22.5                                                                              57                                                         160   185  25                                                       0.01  90  165   175  10  10  81                                                         160   170  10                                                       0.02      165   185  20  20  62                                                         160   180  20                                                       0.01 120  160   175  15  10  81                                                         165   170   5                                                       0.02      165   170   5  12.5                                                                              76                                                         165   185  20                                                       0.01 180  175   180   5  10  81                                                         170   185  15                                                       0.02      170   185  15  17.5                                                                              67                                                         165   185  20                                                       0.01 240  170   175   5  5   91                                                         160   165   5                                                       0.02      165   170   5  10  81                                                         160   175  15                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weiqht(s): 340,340 grams           CONTROL   0.01  0   155   215  60  57.5                                                           165   220  55                                                       0.02      190   230  40  50                                                             175   235  60                                             Ex. No. 3                                                                           10 p.o.                                                                           0.01  30  150   165  15  12.5                                                                              78                                                         175   185  10                                                       0.02      155   175  20  17.5                                                                              65                                                         175   190  15                                                       0.01  60  150   160  10  17.5                                                                              70                                                         155   180  25                                                       0.02      155   180  25  22.5                                                                              55                                                         160   180  20                                                       0.01  90  145   170  20  65  81                                                         160   175  15                                                       0.02      155   205  50  40  20                                                         155   185  30                                                       0.01 120  150   165  15  15  74                                                         160   175  15                                                       0.02      155   210  55  45  10                                                         160   195  35                                                       0.01 180  145   165  20  20  65                                                         155   175  20                                                       0.02      150   190  40  35  30                                                         165   195  30                                                       0.01 240  145   165  20  22.5                                                                              61                                                         160   185  25                                                       0.02      155   200  45  47.5                                                                               5                                                         165   215  50                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 340,360 grams           CONTROL   0.01  0   167   209  42  35                                                             170   198  28                                                       0.02      170   232  62  54.5                                                           177   224  47                                             Ex. No. 3                                                                           10 p.o.                                                                           0.01  30  116   124   8  10  71                                                         172   184  12                                                       0.02      113   128  15  18.5                                                                              66                                                         168   190  22                                                       0.01  60  115   122   7  10.5                                                                              70                                                         170   184  14                                                       0.02      116   133  17  18.5                                                                              66                                                         168   188  20                                                       0.01  90  116   122   6  6.5 81                                                         134   141   7                                                       0.02      160   185  25  24  56                                                         167   190  23                                                       0.01 120  162   172  10  14.5                                                                              59                                                         165   184  19                                                       0.02      160   168   8  10.5                                                                              81                                                         161   174  13                                                       0.01 180  162   162   0  8   77                                                         164   180  16                                                       0.02      156   165   9  13.5                                                                              75                                                         163   181  18                                                       0.01 240  162   168   6  8.5 76                                                         170   181  11                                                       0.02      160   170  10  22.5                                                                              59                                                         175   210  35                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 380,360 grams           CONTROL   0.01  0   147   182  35  40                                                             136   181  45                                                       0.02      150   213  63  54                                                             146   191  45                                             Ex. No. 3                                                                           10 p.o.                                                                           0.01  30  147   157  10  11  73                                                         132   144  12                                                       0.02      148   162  14  16  70                                                         134   152  18                                                       0.01  60  143   155  12  11.5                                                                              71                                                         136   147  11                                                       0.02      151   160   9  22.5                                                                              58                                                         134   170  36                                                       0.01  90  142   154  12  12  70                                                         133   145  12                                                       0.02      145   162  17  17.5                                                                              68                                                         130   148  18                                                       0.01 120  139   154  15  12.5                                                                              69                                                         133   143  10                                                       0.02      136   164  28  22.5                                                                              58                                                         127   144  17                                                       0.01 180  147   160  13  15.5                                                                              61                                                         120   138  18                                                       0.02      144   168  24  25  54                                                         122   148  26                                                       0.01 240  145   163  18  19.5                                                                              51                                                         122   143  21                                                       0.02      144   188  44  35.5                                                                              34                                                         126   153  27                                                       0.01 300  146   166  20  16.5                                                                              59                                                         124   137  13                                                       0.02      153   180  27  24  56                                                         134   155  21                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,390 grams           CONTROL   0.01  0   146   200  54  49                                                             139   183  44                                                       0.02      148   205  57  51.5                                                           146   192  46                                             Ex. No. 3                                                                            3 i.v.                                                                           0.01  30  143   158  15  15  69                                                         124   139  15                                                       0.02      145   166  21  22  57                                                         160   183  23                                                       0.01  60  143   161  18  21  57                                                         131   155  24                                                       0.02      147   185  38  29  44                                                         138   158  20                                                       0.01  90  128   148  20  12  76                                                         148   152   4                                                       0.02      154   188  34  28  46                                                         133   155  22                                                       0.01 120  137   155  18  20.5                                                                              58                                                         148   171  23                                                       0.02      138   161  23  18.5                                                                              64                                                         148   162  14                                                       0.01 180  146   162  16  21  57                                                         139   165  26                                                       0.02      148   179  31  28.5                                                                              45                                                         146   172  26                                                       0.01 240  142   166  24  32  35                                                         132   172  40                                                       0.02      126   145  19  27.5                                                                              47                                                         139   175  36                                                       0.01 300  141   162  21  19  61                                                         146   163  17                                                       0.02      146   179  33  30.5                                                                              41                                                         145   173  28                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 510,510 grams           CONTROL   0.01  0   140   175  35  47.5                                                           142   202  60                                                       0.02      155   194  39  49.5                                                           154   214  60                                             Ex. No. 4                                                                           10 p.o.                                                                           0.01  30  133   173  40  44.5                                                                               6                                                         139   188  49                                                       0.02      154   178  24  36  27                                                         153   201  48                                                       0.01  60  156   177  21  30.5                                                                              36                                                         142   182  40                                                       0.02      156   182  26  44.5                                                                              10                                                         145   208  63                                                       0.01  90  153   180  27  38.5                                                                              19                                                         141   191  50                                                       0.02      163   199  36  52  -5                                                         152   220  68                                                       0.01 120  164   198  34  32.5                                                                              32                                                         146   177  31                                                       0.02      161   194  33  50.5                                                                              -2                                                         146   214  68                                                       0.01 180  149   183  34  35.5                                                                              25                                                         141   178  37                                                       0.02      148   185  37  44  11                                                         141   192  51                                                       0.01 240  148   169  21  29  39                                                         133   170  37                                                       0.02      158   184  26  26  47                                     SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 460,510 grams           CONTROL   0.01  0   137   170  33  31.5                                                           139   169  30                                                       0.02      141   193  52  48                                                             122   166  44                                             Ex. No. 5                                                                           10 i.v.                                                                           0.01  30  141   146   5  5.5 83                                                         120   126   6                                                       0.02      143   155  12  13.5                                                                              72                                                         137   152  15                                                       0.01  60  144   152   8  7.5 76                                                         123   130   7                                                       0.02      144   155  11  10.5                                                                              78                                                         124   134  10                                                       0.01  90  148   155   7  9   71                                                         141   152  11                                                       0.02      146   155   9  8   83                                                         145   152   7                                                       0.01 120  144   158  14  13  59                                                         123   135  12                                                       0.02      148   164  16  15  69                                                         126   140  14                                                       0.01 180  143   156  13  12  62                                                         124   135  11                                                       0.02      145   164  19  19  60                                                         123   142  19                                                       0.01 240  137   155  18  17  46                                                         117   133  16                                                       0.02      135   160  25  23.5                                                                              51                                                         118   140  22                                                       0.01 300  130   161  31  30   5                                                         112   141  29                                                       0.02      139   181  42  39.5                                                                              18                                                         119   156  37                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 460,410 grams           CONTROL   0.01  0   143   189  46  36.5                                                           162   189  27                                                       0.02      151   195  44  42                                                             162   202  40                                             Ex. No. 6                                                                           10 i.v.                                                                           0.01  30  152   158   6  5.5 85                                                         157   162   5                                                       0.02      144   165  21  16  62                                                         147   158  11                                                       0.01  60  150   163  13  7.5 79                                                         177   179   2                                                       0.02      144   170  26  23  45                                                         162   182  20                                                       0.01  90  139   153  14  13.5                                                                              63                                                         155   168  13                                                       0.02      145   168  23  27  36                                                         154   185  31                                                       0.01 120  143   160  17  15  59                                                         154   167  13                                                       0.02      143   176  33  29.5                                                                              30                                                         151   177  26                                                       0.01 180  138   165  27  20.5                                                                              44                                                         152   166  14                                                       0.02      148   189  41  35  17                                                         157   186  29                                                       0.01 240  143   175  32  24  34                                                         163   179  16                                                       0.02      151   199  48  35.5                                                                              15                                                         166   189  23                                                       0.01 300  143   175  32  25.5                                                                              30                                                         165   184  19                                                       0.02      152   193  41  36  14                                                         173   204  31                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 480,520 grams           CONTROL   0.01  0   144   181  37  47                                                             134   191  57                                                       0.02      140   190  50  56                                                             150   212  62                                             Ex. No. 7                                                                           10 i.v.                                                                           0.01  30  141   151  10  6   87                                                         152   154   2                                                       0.02      147   162  15  7.5 87                                                         159   159   0                                                       0.01  60  138   143   5  6   87                                                         148   155   7                                                       0.02      136   145   9  8   86                                                         148   155   7                                                       0.01  90  134   147  13  8.5 82                                                         142   146   4                                                       0.02      137   149  12  12.5                                                                              78                                                         139   152  13                                                       0.01 120  132   142  10  9.5 80                                                         136   145   9                                                       0.02      134   150  16  13  77                                                         141   151  10                                                       0.01 180  136   151  15  17.5                                                                              63                                                         138   158  20                                                       0.02      136   158  22  23  59                                                         134   158  24                                                       0.01 240  129   146  17  20.5                                                                              56                                                         132   156  24                                                       0.02      131   157  26  30.5                                                                              46                                                         143   178  35                                                       0.01 300  128   146  18  20  57                                                         136   158  22                                                       0.02      134   151  17  23  59                                                         145   174  29                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 550,530 grams           CONTROL   0.01  0   142   191  49  37                                                             145   170  25                                                       0.02      152   213  61  51.5                                                           147   189  42                                             Ex. No. 8                                                                           l0 i.v.                                                                           0.01  30  156   178  22  14.5                                                                              61                                                         145   152   7                                                       0.02      150   176  26  23.5                                                                              54                                                         139   160  21                                                       0.01  60  145   154   9  14.5                                                                              61                                                         150   170  20                                                       0.02      145   162  17  21.5                                                                              58                                                         158   184  26                                                       0.01  90  146   154   8  10  73                                                         160   172  12                                                       0.02      142   160  18  17.5                                                                              66                                                         161   178  17                                                       0.01 120  141   154  13  11.5                                                                              69                                                         156   166  10                                                       0.02      139   154  15  15.5                                                                              70                                                         162   178  16                                                       0.01 180  139   156  17  14  62                                                         157   168  11                                                       0.02      140   172  32  28  46                                                         158   182  24                                                       0.01 240  138   151  13  15  59                                                         148   165  17                                                       0.02      143   178  35  29  44                                                         152   175  23                                                       0.01 300  143   161  18  18  51                                                         147   165  18                                                       0.02      153   183  30  28  46                                                         157   183  26                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 585,450 grams           CONTROL   0.01  0   167   183  16  22                                                             162   190  28                                                       0.02      163   193  30  50.5                                                           154   225  71                                             Ex. No. 41                                                                          10 i.v.                                                                           0.01  30  153   164  11  12  45                                                         163   176  13                                                       0.02      161   194  33  23.5                                                                              53                                                         155   169  14                                                       0.01  60  161   171  10  9   59                                                         159   167   8                                                       0.02      156   172  16  18  64                                                         153   173  20                                                       0.01  90  154   169  15  14  36                                                         166   179  13                                                       0.02      151   179  28  22.5                                                                              55                                                         153   170  17                                                       0.01 120  150   160  10  14  36                                                         151   169  18                                                       0.02      149   163  14  16.5                                                                              67                                                         164   183  19                                                       0.01 180  153   167  14  13.5                                                                              39                                                         156   169  13                                                       0.02      154   172  18  21  58                                                         155   179  24                                                       0.01 240  151   162  11  12.5                                                                              43                                                         151   165  14                                                       0.02      156   179  23  23.5                                                                              53                                                         158   182  24                                                       0.01 300  145   160  15  15  32                                                         150   165  15                                                       0.02      150   180  30  27  47                                                         155   179  24                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 400,400 grams           CONTROL   0.01  0   164   209  45  47.5                                                           160   210  50                                                       0.02      186   229  43  51.5                                                           156   216  60                                             Ex. No. 82                                                                          10 i.v.                                                                           0.01  30  156   195  39  36  24                                                         152   185  33                                                       0.02      165   218  53  54  -5                                                         159   214  55                                             Ex. No. 82                                                                          20 i.v.                                                                           0.01  60  162   180  18  15.5                                                                              67                                                         147   160  13                                                       0.02      161   199  38  37  28                                                         151   187  36                                                       0.01  90  158   181  23  23.5                                                                              51                                                         144   168  24                                                       0.02      144   175  31  24  53                                                         143   160  17                                                       0.01 120  157   173  16  16.5                                                                              65                                                         143   160  17                                                       0.02      161   200  39  38.5                                                                              25                                                         152   190  38                                                       0.01 180  149   171  22  18.5                                                                              61                                                         139   154  15                                                       0.02      150   197  47  43.5                                                                              16                                                         130   170  40                                                       0.01 240  144   175  31  29  39                                                         143   170  27                                                       0.02      150   198  48  42  18                                                         146   182  36                                                       0.01 300  152   185  33  32  33                                                         136   167  31                                                       0.02      156   206  50  53                                                             147   203  56                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 470,470 grams           CONTROL   0.01  0   147   191  44  46                                                             163   211  48                                                       0.02      154   212  58  61                                                             160   224  64                                             Ex. No. 84                                                                          10 i.v.                                                                           0.01  30  146   165  19  10.5                                                                              77                                                         172   174   2                                                       0.02      152   168  16  14.5                                                                              76                                                         159   172  13                                                       0.01  60  152   167  15  16.5                                                                              64                                                         154   172  18                                                       0.02      158   201  43  33.5                                                                              45                                                         161   185  24                                                       0.01  90  144   158  14  13  72                                                         153   165  12                                                       0.02      152   173  21  26  57                                                         156   187  31                                                       0.01 120  150   166  16  19.5                                                                              58                                                         143   166  23                                                       0.02      150   175  25  32.5                                                                              47                                                         147   187  40                                                       0.01 180  141   168  27  24.5                                                                              47                                                         149   171  22                                                       0.02      148   170  22  31.5                                                                              48                                                         148   189  41                                                       0.01 240  131   154  23  26  43                                                         143   172      29                                                   0.02      149   186  37  37  39                                                         148   185  37                                                       0.01 300  137   161  24  22.5                                                                              51                                                         151   172  21                                                       0.02      148   i93  45  43  30                                                         150   191  41                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 600,490 grams           CONTROL   0.01  0   144   165  21  26.5                                                           127   159  32                                                       0.02      147   190  43  35.5                                                           137   165  28                                             Ex. No. 85                                                                          10 i.v.                                                                           0.01  30  162   163   1  4.5 83                                                         119   127   8                                                       0.02      156   166  10  9   75                                                         130   138   8                                                       0.01  60  156   162   6  7   74                                                         124   132   8                                                       0.02      156   168  12  9.5 73                                                         129   136   7                                                       0.01  90  151   160   9  9.5 64                                                         125   135  10                                                       0.02      143   150   7  7.5 79                                                         124   132   8                                                       0.01 120  145   152   7  9   66                                                         123   134  11                                                       0.02      139   147   8  6.5 82                                                         127   132   5                                                       0.01 180  125   141  16  15.5                                                                              42                                                         118   133  15                                                       0.02      129   147  18  19.5                                                                              45                                                         106   127  21                                                       0.01 240  129   144  15  12  55                                                         107   116   9                                                       0.02      135   152  17  18  49                                                         108   127  19                                                       0.01 300  129   144  15  12  55                                                         107   116   9                                                       0.02      135   152  17  18  49                                                         108   127  19                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 540,530 grams           CONTROL   0.01  0   141   205  64  62.5                                                           138   199  61                                                       0.02      138   227  89  66.5                                                           143   187  44                                             Ex. No. 87                                                                          10 i.v.                                                                           0.01  30  136   210  74  50  20                                                         145   171  26                                                       0.02      157   227  70  57  14                                                         144   188  44                                             Ex. No. 87                                                                          20 i.v.                                                                           0.01  60  133   150  17  14.5                                                                              77                                                         143   155  12                                                       0.02      150   191  41  32.5                                                                              51                                                         143   167  24                                                       0.01  90  140   163  23  24.5                                                                              61                                                         141   167  26                                                       0.02      148   197  49  33.5                                                                              50                                                         145   163  18                                                       0.01 120  136   162  26  26  58                                                         146   172  26                                                       0.02      152   196  44  35.5                                                                              47                                                         150   177  27                                                       0.01 180  130   163  33  26.5                                                                              58                                                         139   159  20                                                       0.02      148   192  44  37.5                                                                              44                                                         142   173  31                                                       0.01 240  135   172  37  28.5                                                                              54                                                         132   152  20                                                       0.02      136   191  55  41  38                                                         133   160  27                                                       0.01 300  140   177  37  30  52                                                         128   151  23                                                       0.02      138   201  63  48.5                                                                              27                                                         134   168  34                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 480,550 grams           CONTROL   0.01  0   149   178  29  40                                                             158   209  51                                                       0.02      150   213  63  62                                                             161   222  61                                             Ex. No. 89                                                                          10 i.v.                                                                           0.01  30  155   160   5  5   88                                                         160   165   5                                                       0.02      160   170  10  5   92                                                         160   160   0                                                       0.01  60  160   170  10  7.5 81                                                         160   165   5                                                       0.02      155   170  15  10  84                                                         175   180   5                                                       0.01  90  150   155   5  7.5 81                                                         160   170  10                                                       0.02      150   165  15  12.5                                                                              80                                                         160   170  10                                                       0.01 120  140   155  15  15  63                                                         155   170  15                                                       0.02      140   170  30  27.5                                                                              56                                                         155   180  25                                                       0.01 180  135   160  25  25  38                                                         155   180  25                                                       0.02      140   170  30  32.5                                                                              48                                                         155   190  35                                                       0.01 240  135   160  25  25  38                                                         155   180  25                                                       0.02      140   170  30  35  44                                                         150   190  40                                                       0.01 300  130   155  25  27.5                                                                              31                                                         150   180  30                                                       0.02      135   170  35  32.5                                                                              48                                                         160   190  30                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 610,600 grams           CONTROL   0.01  0   144   190  46  48.5                                                           154   205  51                                                       0.02      150   220  70  62.5                                                           160   215  55                                             Ex. No. 91                                                                          10 i.v.                                                                           0.01  30  145   150   5  5   90                                                         150   155   5                                                       0.02      150   160  10  7.5 88                                                         150   155   5                                                       0.01  60  157   160   3  6.5 87                                                         155   165  10                                                       0.02      150   158   8  7   89                                                         155   161   6                                                       0.01  90  155   165  10  9   81                                                         152   160   8                                                       0.02      150   165  15  12.5                                                                              80                                                         150   160  10                                                       0.01 120  150   170  20  13  73                                                         140   146   6                                                       0.02      148   165  17  17.5                                                                              72                                                         142   160  18                                                       0.01 180  142   164  22  22  55                                                         143   165  22                                                       0.02      149   167  18  29  54                                                         145   185  40                                                       0.01 240  146   165  19  20  59                                                         129   150  21                                                       0.02      147   189  42  29.5                                                                              53                                                         135   152  17                                                       0.01 300  146   164  18  16.5                                                                              66                                                         146   161  15                                                       0.02      144   167  23  32.5                                                                              48                                                         147   189  42                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 560,630 grams           CONTROL   0.01  0   158   203  45  49.5                                                           154   208  54                                                       0.02      159   228  69  72                                                             160   235  75                                             Ex. No. 93                                                                          10 i.v.                                                                           0.01  30  160   162   2  2   96                                                         139   141   2                                                       0.02      157   162   5  4.5 94                                                         163   167   4                                                       0.01  60  154   154   0  3   94                                                         163   169   6                                                       0.02      161   166   5  5.5 92                                                         164   170   6                                                       0.01  90  150   155   5  5   90                                                         164   168   5                                                       0.02      154   162   8  7   90                                                         161   167   6                                                       0.01 120  151   156   5  6   88                                                         158   165   7                                                       0.02      155   160   5  7   90                                                         160   169   9                                                       0.01 180  151   161  10  13.5                                                                              73                                                         151   164  13  15.5                                                                              78                                               0.02      151   164  13  15.5                                                                              78                                                         155   173  18                                                       0.01 240  145   158  13  13  74                                                         156   169  13                                                       0.02      148   166  18  17  76                                                         158   174  16                                                       0.01 300  146   158  12  12  76                                                         156   168  12                                                       0.02      144   162  18  18.5                                                                              74                                                         154   173  19                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 580,480 grams           CONTROL   0.01  0   155   202  47  45.5                                                           165   209  44                                                       0.02      160   225  65  61                                                             172   229  57                                             Ex. No. 95                                                                          10 i.v.                                                                           0.01  30  163   193  30  29.5                                                                              35                                                         168   197  29                                                       0.02      170   225  55  56   8                                                         170   227  57                                             Ex.No. 95                                                                           20 i.v.                                                                           0.01  60  154   171  17  15  67                                                         156   169  13                                                       0.02      160   177  17  19.5                                                                              68                                                         162   184  22                                                       0.01  90  154   168  14  13.5                                                                              70                                                         167   180  13                                                       0.02      158   177  19  24  61                                                         164   193  29                                                       0.01 120  147   167  20  24  47                                                         161   189  28                                                       0.02      153   174  21  28.5                                                                              53                                                         161   197  36                                                       0.01 180  146   168  22  23.5                                                                              48                                                         156   181  25                                                       0.02      154   189  35  34  44                                                         161   194  33                                                       0.01 240  151   168  17  21.5                                                                              53                                                         154   180  26                                                       0.02      153   189  36  34  44                                                         165   197  32                                                       0.01 300  142   165  23  24.5                                                                              46                                                         151   177  26                                                       0.02      148   193  45  37.5                                                                              39                                                         163   193  30                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 470,470 grams           CONTROL   0.01  0   134   163  29  32.5                                                           144   180  36                                                       0.02      137   193  56  57  5                                                          153   212  59                                             Ex. No.96                                                                           10 i.v.                                                                           0.01  30  144   157  13  11.5                                                                              65                                                         143   153  10                                                       0.02      139   150  11  19.5                                                                              66                                                         148   176  28                                                       0.01  60  141   149   8  7   78                                                         149   155   6                                                       0.02      140   155  15  12.5                                                                              78                                                         148   158  10                                                       0.01  90  133   148  15  13.5                                                                              58                                                         146   163  17                                                       0.01 120  134   148  14  13.5                                                                              58                                                         146   159  13                                                       0.02      137   151  14  17.5                                                                              70                                                         148   169  21                                                       0.01 180  136   153  17  15.5                                                                              52                                                         140   154  14                                                       0.02      139   153  14  16  72                                                         136   154  18                                                       0.01 240  133   152  19  18.5                                                                              43                                                         138   156  18                                                       0.02      136   173  37  39.5                                                                              31                                                         145   187  42                                                       0.01 300  138   154  16  15.5                                                                              52                                                         137   152  15                                                                 147   184  37  42  27                                                         138   185  47                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,440 grams           CONTROL   0.01  0   158   181  23  29                                                             148   183  35                                                       0.02      161   198  37  48                                                             151   210  59                                             Ex. No. 116                                                                         10 i.v.                                                                           0.01  30  160   181  21  22.5                                                                              22                                                         162   186  24                                                       0.02      160   191  31  36.5                                                                              24                                                         156   198  42                                                       0.01  60  158   180  22  18  38                                                         156   170  14                                                       0.02      160   197  37  33.5                                                                              30                                                         160   190  30                                                       0.01  90  159   182  23  19  34                                                         157   172  15                                                       0.02      163   201  38  32  33                                                         162   188  26                                                       0.01 120  157   175  18  19.5                                                                              33                                                         158   179  21                                                       0.02      154   203  49  40  17                                                         167   198  31                                                       0.01 180  153   170  17  18  38                                                         157   176  19                                                       0.02      155   201  46  40  17                                                         176   210  34                                                       0.01 240  153   169  16  16  45                                                         156   172  16                                                       0.02      152   188  36  38.5                                                                              20                                                         156   197  41                                                       0.01 300  153   176  23  22  24                                                         127   148  21                                                       0.02      154   205  51  41.5                                                                              14                                                         163   195  32                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 460,570 grams           CONTROL   0.01  0   146   184  38  36.5                                                           156   191  35                                                       0.02      146   210  64  56.5                                                           160   209  49                                             Ex. No. 117                                                                         10 i.v.                                                                           0.01  30  154   195  41  36   1                                                         1623  193  31                                                       0.02      154   220  66  63  -12                                                        162   222  60                                                   20 i.v.                                                                           0.01  60  154   182  28  36   1                                                         164   208  44                                                       0.02      157   197  40  40  29                                                         173   213  40                                                       0.01  90  158   174  16  22.5                                                                              38                                                         162   191  29                                                       0.02      160   208  48  46  19                                                         165   209  44                                                       0.01 120  151   171  20  23  37                                                         154   180  26                                                       0.02 150  183   33   38  33                                                             158   201  43                                                       0.01 180  141   168  27  26.5                                                                              27                                                         150   176  26                                                       0.02      143   185  42  46  19                                                         151   201  50                                                       0.01 240  139   168  29  25  32                                                         146   167  21                                                       0.02      143   175  32  40.5                                                                              28                                                         146   195  49                                                       0.01 300  137   164  27  26  29                                                         149   174  25                                                                 144   183  39  42.5                                                                              25                                                         149   195  46                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 570,460 grams           CONTROL   0.01  0   135   171  36  34.5                                                           121   154  33                                                       0.02      138   184  46  47.5                                                           156   205  49                                             Ex. No. 157                                                                         10 i.v.                                                                           0.01  30  136   175  39  26  25                                                         152   165  13                                                       0.02      148   199  51  38  20                                                         153   178  25                                                       0.01  60  150   179  29  26.5                                                                              23                                                         135   159  24                                                       0.02      160   191  31  31.5                                                                              34                                                         153   185  32                                                       0.01  90  145   167  22  21  39                                                         161   181  20                                                       0.02      148   185  37  40  16                                                         152   195  43                                                       0.01 120  136   161  25  26.5                                                                              23                                                         138   166  28                                                       0.02      140   183  43  39.5                                                                              17                                                         150   186  36                                                       0.01 180  131   164  33  32.5                                                                               6                                                         132   164  32                                                       0.02      137   185  48  52  -9                                                         140   196  56                                                       0.01 240  140   167  27  28.5                                                                              17                                                         155   185  30                                                       0.02      138   167  29  35.5                                                                              25                                                         143   185  42                                                       0.01 300  138   162  24  25.5                                                                              26                                                         141   168  27                                                       0.02      146   176  30  40  16                                                         156   206  50                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 400,470 grams           CONTROL   0.01  0   146   191  45  41                                                             161   198  37                                                       0.02      157   207  50  50                                                             163   213  50                                             Ex. No. 357                                                                         10 i.v.                                                                           0.01  30  144   159  15  16.5                                                                              60                                                         167   185  18                                                       0.02      145   169  24  16  68                                                         164   172   8                                                       0.01  60  156   160   4  4.5 89                                                         164   169   5                                                       0.02      145   159  14  10.5                                                                              79                                                         164   171   7                                                       0.01  90  142   153  11  8   80                                                         167   172   5                                                       0.02      143   154  11  10.5                                                                              79                                                         168   178  10                                                       0.01 120  140   151  11  8   80                                                         165   170   5                                                       0.02      136   139   3  6   88                                                         165   174   9                                                       0.01 180  147   154  12  11  78                                                         162   172  10                                                       0.01 240  145   159  14  14  66                                                         159   173  14                                                       0.02      157   174  17  14.5                                                                              71                                                         160   172  12                                                       0.01 300  148   164  16  16  61                                                         151   167  16                                                       0.02      148   169  21  16  68                                                         158   169  11                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,460 grams           CONTROL   0.01  0   139   190  51  36.5                                                           159   181  22                                                       0.02      155   212  57  39.5                                       Ex. No. 358                                                                         10 i.v.                                                                           0.01  30  147   163  16  12  67                                                         161   169   8                                                       0.02      149   169  20  24  39                                                         162   190  28                                                       0.01  60  145   153   8  13  64                                                         153   171  18                                                       0.02      142   155  13  10  75                                                         160   167   7                                                       0.01  90  142   157  25  17.5                                                                              52                                                         156   166  10                                                       0.02      148   161  13  11  72                                                         161   170   9                                                       0.01 120  144   153   9  8   78                                                         159   166   7                                                       0.02      139   155  16  14  65                                                         155   167  12                                                       0.01 180  134   158  24  17.5                                                                              52                                                         147   158  11                                                       0.02      146   162  16  14.5                                                                              63                                                         154   167  13                                                       0.01 240  139   153  14  12  67                                                         143   153  10                                                       0.02      144   162  18  15.5                                                                              61                                                         145   158  13                                                       0.01 300  137   163  26  19  48                                                         137   149  12                                                       0.02      140   158  18  16  59                                                         141   155  14                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 520,515 grams           CONTROL   0.01  0   141   165  24  23.5                                                           145   168  23                                                       0.02      145   182  37  37                                                             153   190  37                                             Ex. No. 384                                                                         10 i.v.                                                                           0.01  30  145   157  12  9   62                                                         156   162   6                                                       0.02      150   168  18  14.5                                                                              61                                                         158   169  11                                                       0.01  60  151   160   9  9   62                                                         158   167   9                                                       0.02      152   162  10  10.5                                                                              72                                                         160   171  11                                                       0.01  90  154   170  16  12  49                                                         160   168   8                                                       0.02      157   177  20  15.5                                                                              58                                                         162   173  11                                                       0.01 120  149   159  10  10.5                                                                              55                                                         131   142  11                                                       0.02      150   162  12  11  53                                                         164   175  11                                                       0.01 180  150   162  12  11  53                                                         158   168  10                                                       0.02      156   167  11  13.5                                                                              64                                                         160   176  16                                                       0.01 240  145   156  11  11  53                                                         155   166  11                                                       0.02      145   161  16  15  59                                                         160   174  14                                                       0.01 300  148   162  14  12  49                                                         152   162  10                                                       0.02      151   168  17  17  54                                                         158   175  17                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 455,500 grams           CONTROL   0.01  0    96   135  39  36                                                             151   184  33                                                       0.02      131   154  23  36                                                             158   207  49                                             Ex. No. 407                                                                         10 i.v.                                                                           0.01 30   120   131  11  9.5 74                                                         150   158   8                                                       0.02      132   142  10  13  64                                                         153   169  16                                                       0.01  60  112   139  27  25.5                                                                              29                                                         150   174  24                                                       0.02      128   131   3  10  72                                                         154   171  17                                                       0.01  90   90   114  24  19  47                                                         152   166  14                                                       0.02       87   122  35  26.5                                                                              26                                                         154   172  18                                                       0.01 120  120   127   7  8.5 76                                                         145   155  10                                                       0.02      113   127  14  17  53                                                         147   167  20                                                       0.01 180  112   124  12  11.5                                                                              68                                                         141   152  11                                                       0.02      109   129  20  20  44                                                         139   159  20                                                       0.01 240  114   130  16  18  50                                                         131   151  20                                                       0.02      120   136  16  21.5                                                                              40                                                         142   169  27                                                       0.01 300  115   130  15  20  44                                                         130   155  25                                                       0.02      116   137  21  22.5                                                                              38                                                         136   160  24                                             SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 470,550                 __________________________________________________________________________    grams                                                                     

                  TABLE XVI                                                       ______________________________________                                        VASOPRESSIN (VAS) VASOPRESSOR RESPONSE                                        Ex. No. Dose mg/kg  Max. % Inhibition                                                                          Time (min)                                   ______________________________________                                         2       30 i.v.    74           120                                           9       10 i.v.    95           60                                            17      30 i.v.    50           60                                            36      10 i.v.    76           120                                           99      10 i.v.    76           120                                          210      10 i.v.    78           90                                           217      30 i.v.    57           90                                           271      10 i.v.    56           60                                           274      10 i.v.    59           300                                          465      10 i.v.    85           90                                           466      30 i.v.    94           94                                           467      10 i.v.    65           120                                          468      10 i.v.    68           30                                           469      10 i.v.    69           30                                           470      10 i.v.    87           180                                                   30 p.o.    69           180                                          471      30 i.v.    85           90                                           472      30 i.v.    36           90                                           474      30 i.v.    80           60                                           476      10 i.v.    78           30                                                    30 p.o.    19           180                                          477      10 i.v.    88           180                                                   30 p.o.    82           30                                           478      10 i.v.    76           120                                          479      10 i.v.    83           60                                                    30 p.o.    69           90                                           480      10 i.v.    29           300                                          481      30 p.o.    58           80                                           482      10 i.v.    40           60                                           484      10 i.v.    79           300                                                   30 p.o.    22           180                                          485      30 i.v.    64           60                                           488      30 i.v.    43           60                                           489      30 i.v.    39           120                                          490      10 i.v.    74           90                                                    10 p.o.    65           120                                          517      10 i.v.    81           90                                           525      30 i.v.    70           60                                           527      30 i.v.    85           180                                          528      30 i.v.    66           300                                          530      30 i.v.    89           120                                          581      10 i.v.    94           30                                                    30 p.o.    79           30                                           582      10 i.v.    75           180                                          585      10 i.v.    56           30                                           587      10 i.v.    75           60                                           588      10 i.v.    65           90                                                    30 p.o.    80           120                                          590      30 i.v.    89           120                                          592      30 i.v.    37           90                                           593      30 i.v.    67           60                                           594      30 i.v.    36           180                                          595      30 i.v.    44           90                                           599      30 i.v.    86           90                                           600      30 i.v.    78           60                                           ______________________________________                                    

Oxytocin Receptor Binding

(a) Membrane Preparation

Female Sprague-Dawley rats weighing approximately 200-250 g are injectedintramuscularly (i.m.) with 0.3 mg/kg of body weight ofdiethylstilbestrol (DES). The rats are sacrificed 18 hours later underpentobarbital anesthesia. The uteri are dissected out, cleaned of fatand connective tissues and rinsed in 50 ml of normal saline. The tissuepooled from six rats is homogenized in 50 ml of 0.01 mM Tris. HCl,containing 0.5 mM dithiothreitol and 1.0 mM EDTA, adjusted to pH 7.4,using a polytron at setting 6 with three passes of 10 sec each. Thehomogenate is passed through two (2) layers of cheesecloth and thefiltrate centrifuged at 1000×g for 10 min. The clear supernatant isremoved and recentrifuged at 165,000×g for 30 min. The resulting pelletcontaining the oxytocin receptors is resuspended in 50.0 mM Tris. HClcontaining 5.0 mM MgCl₂ at pH 7.4, to give a protein concentration of2.5 mg/ml of tissue suspension. This preparation is used in subsequentbinding assays with ³ H!Oxytocin.

(b) Radioligand Binding

Binding of 3,5- ³ H!Oxytocin ( ³ H!OT) to its receptors is done inmicrotiter plates using ³ H!OT, at various concentrations, in an assaybuffer of 50.0 mM Tris.HCl, pH 7.4 and containing 5.0 mM MgCl₂, and amixture of protease inhibitors: BSA, 0.1 mg; aprotinin, 1.0 mg;1,10-phenanthroline, 2.0 mg; trypsin, 10.0 mg; and PMSF, 0.3 mg per 100ml of buffer solution. Non-specific binding is determined in thepresence of 1.0 uM unlabeled OT. The binding reaction is terminatedafter 60 min., at 22° C., by rapid filtration through glass fiberfilters using a Brandel® cell harvester (Biomedical Research andDevelopment Laboratories, Inc., Gaithersburg, Md.). Competitionexperiments are conducted at equilibrium using 1.0 nM ³ H!OT and varyingthe concentration of the displacing agents. The concentrations of agentdisplacing 50% of ³ H!OT at its sites (IC₅₀) are calculated by acomputer assisted LUNDON-2 program (LUNDON SOFTWARE INC., Ohio, USA).

The results of this assay on representative examples are shown in TableXVII.

                  TABLE XVII                                                      ______________________________________                                        Oxytocin                                                                               Dose         % Inhibition                                            Ex. No.  (μM)      at 10 μM                                                                             IC.sub.50                                     ______________________________________                                         3       10           90        0.36                                           4       10           98        0.66                                           6       10           92        0.35                                           7       10           97        0.13                                           17      10           31                                                       36      10           67        2.45                                           54      10           94        0.16                                           85      10           98        0.46                                           93      10           87        0.06                                           96      10           94        1.2                                           160      10           31                                                      164      10           67        2.45                                          210      20           64        4                                             214      10           64        4                                             215      10           74        0.57                                          217      10           87        1.2                                           274      10           95        1                                             297      10           76        4                                             298      10           76        4                                             416      10           44.6      7.4                                           417      10           21                                                      418      10           39                                                      419      10           28                                                      420      10           16                                                      429      10           11                                                      430      10           16                                                      431      10           18                                                      432      10           19                                                      433      10           12                                                      435      10           10                                                      436      10           32                                                      441      1            22                                                      443      10           70                                                      444      10           21                                                      448      10           11                                                      449      10           14                                                      450      10           22                                                      451      10           43                                                      452      10           36                                                      455      10           75        2.9                                           360      10           77        3.1                                           461      10           44.6      7.4                                           462      10           14                                                      463      10           55        8.5                                           464      10           71        2.4                                           465      10           93        0.033                                         468      10           96        0.26                                          469      10           96        0.265                                         470      2.5          92        0.22                                          471      10           99        0.35                                          472      10           0                                                       473      10           20                                                      474      10           18                                                      476      10           94        0.82                                          477      1.25         97        0.029                                         278      1.25         97        0.04                                          479      10           76        0.15                                          480      10           98        0.15                                          481      10           88        0.24                                          482      10           97        0.126                                         485      10           86        2.2                                           486      10           18                                                      489      10           44                                                      490      10           99        0.3                                           491      10           46                                                      517      10           91        0.32                                          519      10           97        0.48                                          520      10           79        2.2                                           524      10           84        1.8                                           525      10           98        0.28                                          526      10           97        0.47                                          527      10           92        0.45                                          528      10           90        1.17                                          529      10           92        0.45                                          530      10           99        0.31                                          538      10           90        0.9                                           546      10           91        0.99                                          547      5            97        0.26                                          580      10           79        2.96                                          581      10           99        0.2                                           582      10           96        0.675                                         583      10           61        4                                             584      10           26                                                      585      10           70        4.7                                           586      10           61        4.7                                           587      10           56        8                                             588      10           90        2                                             589      10           79        2.9                                           590      10           12                                                      591      10           29                                                      592      10           41                                                      593      10           82        1.1                                           594      10           19                                                      595      10           49                                                      596      10           86        4                                             597      10           42                                                      598      10           2                                                       599      10           92        0.35                                          609      10           66        2.7                                           664      10           95        1.4                                           665      10           97        1                                             666      10           83        2.1                                           667      10           89        1.6                                           676      10           32                                                      ______________________________________                                    

The compounds of the present invention can be used in the form of saltsderived from pharmaceutically or physiologically acceptable acids orbases. These salts include but are not limited to the following: saltswith inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid and, as the case may be, such organic acids asacetic acid, oxalic acid, succinic acid, and maleic acid. Other saltsinclude salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium or with organic bases. Thecompounds can also be used in the form of esters, carbamates and otherconventional "pro-drug" forms, which, when administered in such form,convert to the active moiety in vivo.

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, forexample, solvents, diluents and the like, and may be administered orallyin such forms as tablets, capsules, dispersible powders, granules, orsuspensions containing, for example, from about 0.05 to 5% of suspendingagent, syrups containing, for example, from about 10 to 50% of sugar,and elixirs containing, for example, from about 20 to 50% ethanol, andthe like, or parenterally in the form of sterile injectable solution orsuspension containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 0.05 up to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.5 to about 500 mg/kgof animal body weight, preferably given in divided doses two to fourtimes a day, or in sustained release form. For most large mammals thetotal daily dosage is from about 1 to 100 mg, preferably from about 2 to80 mg. Dosage forms suitable for internal use comprise from about 0.5 to500 mg of the active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier. This dosage regimen may beadjusted to provide the optimal therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterallyor-intraperitoneally. Solutions or suspensions of these active compoundsas a free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparation contain a preservative to prevent thegrowth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol(e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

We claim:
 1. A compound selected from Formula I: ##STR293## wherein;A--B is ##STR294## the moiety ##STR295## represents a fused phenyl orfused substituted phenyl optionally substituted by one or twosubstituents selected from (C₁ -C₃) lower alkyl, halogen, amino, (C₁-C₃) lower alkoxy, or (C₁ -C₃) lower alkylamino;the moiety: ##STR296##is a five-membered aromatic (unsaturated) fused nitrogen-containingheterocyclic ring wherein D, E, and F are carbon and wherein the carbonatoms may be optionally substituted by a substituent selected fromhalogen, (C₁ -C₃) lower alkyl, hydroxy, COCCl₃, COCF₃, ##STR297## --CHO,amino, (C₁ -C₃) lower alkoxy, (C₁ -C₃) lower alkylamino, CONH (C₁ -C₃)lower alkyl, or --CON lower alkyl (C₁ -C₃)!₂, R_(b) is independentlyselected from H, --CH₃, or --C₂ H₅ ; q is 1 or 2; R₃ is the moiety##STR298## wherein Ar is a moiety selected from the group ##STR299## andX is selected from O, S, NH, --NCH₃, or --N--COCH₃ ; R₄ is selected fromH, lower alkyl (C₁ -C₃), --CO-lower alkyl (C₁ -C₃), SO₂ lower alkyl (C₁-C₃), or the moieties of the formulae: ##STR300## R₁ and R₂ are,independently, H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy, orhalogen; R₅ is H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy orhalogen; R₆ is selected from:(a) moieties of the formula: ##STR301##wherein cycloalkyl is defined as C₃ to C₆ cycloalkyl, cyclohexenyl orcyclopentenyl; n is 0-2; R_(a) is independently selected from H, --CH₃,--C₂ H₅, ##STR302## --(CH₂)_(q) --O-lower alkyl (C₁ -C₃), or --CH₂ CH₂OH; R_(b) is as hereinbefore defined; q is 1 or 2;(b) a moiety of theformula: ##STR303## where R₂ is as hereinbefore defined; (c) a moiety ofthe formula: ##STR304## wherein J is R_(a), lower alkyl (C₁ -C₈)branched or unbranched, lower alkenyl (C₂ -C₈) branched or unbranched,--O-lower alkyl (C₁ -C₈) branched or unbranched, --O-lower alkenyl (C₂-C₈) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or--CH₂ --K wherein K is halogen, (C₁ -C₃) lower alkoxy, tetrahydrofuran,tetrahydrothiophene or the heterocyclic ring moiety: ##STR305## whereinD, E, F and G are selected from carbon or nitrogen and wherein thecarbon atoms may be optionally substituted with halogen, (C₁ -C₃)loweralkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO, (C₁ -C₃)lower alkoxy, or--CO₂ -lower alkyl (C₁ -C₃); and R_(a) and R_(b) are as hereinbeforedefined;(d) a moiety selected from those of the formulae: ##STR306##wherein R_(c) is selected from halogen, (C₁ -C₃)lower alkyl, --O-loweralkyl (C₁ -C₃), OH ##STR307## q is 1 or 2; R_(a) and R_(b) are ashereinbefore defined; wherein Ar' is selected from the group: ##STR308##wherein W' is selected from O, S, NH, N-lower alkyl (C₁ -C₃),--NHCO-lower alkyl (C₁ -C₃), or NSO₂ -lower alkyl (C₁ -C₃); R⁷ isselected from H, lower alkyl (C₁ -C₃), halogen, --O-lower alkyl (C₁-C₃), or CF₃ ; R⁸ and R⁹ are independently selected from hydrogen, loweralkyl (C₁ -C₃), S-lower alkyl (C₁ -C₃), halogen, --NH-lower alkyl (C₁-C₃), --OCF₃, --CN, --OH, --S--CF₃, --NO₂, NH₂, or --O-lower alkyl (C₁-C₃); R¹⁰ is H, halogen, or lower alkyl-(C₁ -C₃);and thepharmaceutically acceptable salts, esters and pro-drug forms thereof. 2.A compound according to claim 1 wherein R³ is the moiety: ##STR309## andAr is the moiety ##STR310## wherein R⁵, R⁶, and R⁷ are as defined inclaim 1 or a pharmaceutically acceptable salt, ester or pro-drug formthereof.
 3. A compound according to claim 1 wherein R³ is the moiety:##STR311## and Ar is the moiety ##STR312## wherein R⁵, R⁶, and R⁷ are asdefined in claim 1 and Ar' is selected from the moieties ##STR313##wherein R⁵, R⁸, R⁹ and W' are as defined in claim 1, or apharmaceutically acceptable salt, ester or pro-drug form thereof.
 4. Acompound according to claim 1 wherein R³ is the moiety: ##STR314## andAr is the moiety ##STR315## wherein R⁵ and R⁷ are as defined in claim 1and R⁶ is selected from:(a) moieties of the formula: ##STR316## whereincycloalkyl is defined as C₃ to C₆ cycloalkyl, cyclohexenyl orcyclopentenyl; n is 0-2; R_(a) is independently selected from H, --CH₃,--C₂ H₅, ##STR317## --(CH₂)_(q) lower alkyl (C₁ C₃), or --CH₂ CH₂ OH; qis 1 or 2; R_(b) is selected from H, --CH₃, or C₂ H₅ ; or(b) a moiety ofthe formula: ##STR318## wherein J is R_(a), lower alkyl (C₁ -C₈)branched or unbranched, lower alkenyl (C₂ -C₈) branched or unbranched,--O-lower alkyl (C₁ -C₈) branched or unbranched, --O-lower alkenyl (C₂-C₈) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or--CH₂ --K wherein K is halogen, (C₁ -C₃) lower alkoxy, tetrahydrofuran,tetrahydrothiophene or the heterocyclic ring moiety: ##STR319## whereinD, E, F and G are selected from carbon or nitrogen and wherein thecarbon atoms may be optionally substituted with halogen, (C₁ -C₃)loweralkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO, (C₁ -C₃)lower alkoxy, or--CO₂ -lower alkyl (C₁ -C₃); and R_(a) and R_(b) are as hereinbeforedefined; or(c) a moiety selected from those of the formulae: ##STR320##wherein R_(c) is selected from halogen, (C₁ -C₃) lower alkyl, --O-loweralkyl (C₁ -C₃), OH, ##STR321## q is 1 or 2; and R_(a) and R_(b) are ashereinbefore defined; wherein Ar' is selected from the group: ##STR322##wherein R⁸, R⁹ and W' are as defined in claim 1, or a pharmaceuticallyacceptable salt, ester or pro-drug form thereof.
 5. The compoundaccording to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methylbenzamide.
 6. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-chlorobenzamide.
 7. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,5-dichlorobenzamide.
 8. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,4-dichlorobenzamide.
 9. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-chloro-4-methylbenzamide. 10.The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methyl-4-chlorobenzamide. 11.The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,4-dimethylbenzamide.
 12. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,3-dimethylbenzamide.
 13. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methoxybenzamide.
 14. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-trifluoromethoxybenzamide. 15.The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,4-dimethoxybenzamide.
 16. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,6-dimethoxybenzamide.
 17. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,6-dichlorobenzamide.
 18. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2,6-dimethylbenzamide.
 19. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methylthiobenzamide.
 20. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methyl-3-thiophenecarboxamide.21. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-3-methyl-2-thiophenecarboxamide.22. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methyl-3-furanecarboxamide.23. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-3-methyl-2-furanecarboxamide.24. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a! 1,5!benzodiazepin-5-yl)carbonyl!phenyl!benzeneacetamide.
 25. Thecompound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-chlorobenzeneacetamide. 26.The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methylbenzeneacetamide. 27.The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!phenyl!-2-methyl-3-thiopheneacetamide.28. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2,5-dichlorophenyl!-2,3-dimethylbenzamide.29. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2,5-dichlorophenyl!-2-chlorobenzamide.30. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2,5-dichlorophenyl!-2,4-dichlorobenzamide.31. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2,5-dichlorophenyl!-3,5-dichlorobenzamide.32. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2,5-dichlorophenyl!-2-methyl-4-chlorobenzamide.33. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methoxybenzamide. 34.The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)-carbonyl!-3-chlorophenyl!-2-(trifluoromethoxy)benzamide.35. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-(trifluoromethyl)benzamide.36. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,4-dichlorobenzamide.37. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-(methylthio)benzamide.38. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-3-fluoro-2-methylbenzamide.39. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-5-fluoro-2-methylbenzamide.40. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-4-fluoro-2-methylbenzamide.41. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)-carbonyl!-3-chlorophenyl!-4-fluoro-2-(trifluoromethyl)benzamide.42. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)-carbonyl!-3-chlorophenyl!-2,3-dichlorobenzamide.43. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,3-difluorobenzamide.44. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-fluoro-5-(trifluoromethyl)benzamide.45. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-fluoro-3-(trifluoromethyl)benzamide.46. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-4-fluoro-2-(trifluoromethyl)benzamide.47. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,5-difluorobenzamide.48. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,3-difluorobenzamide.49. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2,5-dimethylbenzamide.50. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-3-methyl-2-thiophenecarboxamide.51. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-thiophenecarboxamide.52. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methyl-3-furanecarboxamide.53. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-3-methyl-2-furanecarboxamide.54. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-chlorobenzeneacetamide.55. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-2-methylbenzeneacetamide.56. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-chlorophenyl!-4-fluoro-3-(trifluoromethyl)benzamide.57. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-3-fluoro-2-methylbenzamide.58. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,3-dichlorobenzamide.59. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,3-difluorobenzamide.60. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-4-fluoro-2-methylbenzamide.61. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-5-fluoro-2-methylbenzamide.62. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-fluoro-5-(trifluoromethyl)benzamide.63. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-methylbenzamide. 64.The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-chlorobenzamide. 65.The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,3-dimethylbenzamide.66. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,5-dimethylbenzamide.67. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-methoxybenzamide. 68.The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo 1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-(trifluoromethoxy)benzamide.69. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-methoxy-4-chlorobenzamide.70. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,6-dichlorobenzamide.71. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-(methylthio)benzamide.72. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2-(trifluoromethyl)benzamide.73. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-3-(trifluoromethyl)benzamide.74. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-chlorophenyl!-2,3,5-trichlorobenzamide.75. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-3-fluoro-2-methylbenzamide.76. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-5-fluoro-2-methylbenzamide.77. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-4-fluoro-2-methylbenzamide.78. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-2,4-dichlorobenzamide.79. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-2,3-dimethylbenzamide.80. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-3-methoxyphenyl!-3-fluoro-5-(trifluoromethyl)benzamide.81. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-3-fluoro-2-methylbenzamide.82. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-5-fluoro-2-methylbenzamide.83. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-4-fluoro-2-methylbenzamide.84. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-2,4-dichlorobenzamide.85. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-2,3-dimethylbenzamide.86. The compound according to claim 1, N- 4- (6,7-dihydro-5H-pyrrolo1,2-a!1,5!benzodiazepin-5-yl)carbonyl!-2-methoxyphenyl!-3-fluoro-5-(trifluoromethyl)benzamide.87. A pharmaceutical composition useful for treating disease in a mammalcharacterized by excess renal reabsorption of water, the pharmaceuticalcomposition comprising an effective amount of a compound of claim 1, ora pharmaceutically acceptable salt, ester or prodrug form thereof, and asuitable pharmaceutical carrier.
 88. The pharmaceutical composition ofclaim 87 wherein the disease in a mammal characterized by excess renalreabsorption of water is congestive heart failure, nephrotic syndrome,hyponatremia, coronary vasospasm, cardiac ischemia, renal vasospasm,liver cirrhosis, brain edema, cerebral ischemia, or cerebralhemorrhage-stroke.
 89. A method for treating disease in a mammalcharacterized by excess renal reabsorption of water, the methodcomprising administering to a mammal in need thereof an effective amountof a compound of claim 1, or a pharmaceutically acceptable salt, esteror prodrug form thereof, and a suitable pharmaceutical carrier.
 90. Themethod of claim 89 wherein the disease in a mammal characterized byexcess renal reabsorption of water is congestive heart failure,nephrotic syndrome, hyponatremia, coronary vasospasm, cardiac ischemia,renal vasospasm, liver cirrhosis, brain edema, cerebral ischemia, orcerebral hemorrhage-stroke.